8 results on '"IALENTI, ARMANDO"'
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2. Novel benzoxanthene lignans that favorably modulate lipid mediator biosynthesis: A promising pharmacological strategy for anti-inflammatory therapy.
- Author
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Gerstmeier J, Kretzer C, Di Micco S, Miek L, Butschek H, Cantone V, Bilancia R, Rizza R, Troisi F, Cardullo N, Tringali C, Ialenti A, Rossi A, Bifulco G, Werz O, and Pace S
- Subjects
- Adult, Animals, Arachidonate 5-Lipoxygenase physiology, Arthritis, Rheumatoid drug therapy, HEK293 Cells, Humans, Leukocytes metabolism, Macrophages metabolism, Mice, Prostaglandin-E Synthases antagonists & inhibitors, Anti-Inflammatory Agents pharmacology, Leukotrienes biosynthesis, Lignans pharmacology
- Abstract
Lipid mediators (LM) encompass pro-inflammatory prostaglandins (PG) and leukotrienes (LT) but also specialized pro-resolving mediators (SPM) which display pivotal bioactivities in health and disease. Pharmacological intervention with inflammatory disorders such as osteoarthritis and rheumatoid arthritis commonly employs anti-inflammatory drugs that can suppress PG and LT formation, which however, possess limited effectiveness and side effects. Here, we report on the discovery and characterization of the two novel benzoxanthene lignans 1 and 2 that modulate select LM biosynthetic enzymes enabling the switch from pro-inflammatory LT to SPM biosynthesis as potential pharmacological strategy to intervene with inflammation. In cell-free assays, compound 1 and 2 inhibit microsomal prostaglandin E
2 synthase-1 and leukotriene C4 synthase (IC50 ∼ 0.6-3.4 µM) and potently interfere with 5-lipoxygenase (5-LOX), the key enzyme in LT biosynthesis (IC50 = 0.04 and 0.09 µM). In human neutrophils, monocytes and M1 and M2 macrophages, compound 1 and 2 efficiently suppress LT biosynthesis (IC50 < 1 µM), accompanied by elevation of 15-LOX-derived LM including SPM. In zymosan-induced murine peritonitis, compound 1 and 2 ameliorated self-limited inflammation along with suppression of early LT formation and elevation of subsequent SPM biosynthesis in vivo. Together, these novel benzoxanthene lignans promote the LM class switch from pro-inflammatory towards pro-resolving LM to terminate inflammation, suggesting their suitability as novel leads for pharmacotherapy of arthritis and related inflammatory disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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3. The relatively selective cyclooxygenase-2 inhibitor nimesulide: What's going on?
- Author
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Caiazzo E, Ialenti A, and Cicala C
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Cyclooxygenase 2 metabolism, Cyclooxygenase 2 Inhibitors chemistry, Gastrointestinal Agents chemistry, Gastrointestinal Agents pharmacology, Humans, Neutrophils drug effects, Neutrophils enzymology, Sulfonamides chemistry, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cyclooxygenase 2 Inhibitors pharmacology, Sulfonamides pharmacology
- Abstract
Nimesulide is a relatively selective cyclooxygenase (COX)-2 inhibitor, non-steroidal anti-inflammatory drug; it has been discovered in 1971 and firstly commercialized in Italy in 1985. There is much evidence that the pharmacological profile of nimesulide is peculiar and not shared with the other COX-2 selective inhibitors, suggesting that other molecular mechanisms besides inhibition of COX-2 derived prostaglandins are involved. Similarly, experimental data suggest that the gastrointestinal safety of nimesulide cannot be ascribed only to a COX-1 sparing effect. On the inflammatory process, the efficacy of nimesulide is dependent upon a wide spectrum of actions, due to the combination of effects on immune and non-immune cells. Early data demonstrated a central role for cyclic AMP (cAMP) in the anti-inflammatory effect of nimesulide; more recently, we have shown the involvement of the pathway ecto-5'-nucleotidase/adenosine A
2A receptor. To date, the molecular mechanism(s) that confers uniqueness to nimesulide have not yet been defined. To go inside the mechanism of action of an existing drug, such as nimesulide, would be helpful to refine its therapeutic use but also to identify new targets for novel therapeutic anti-inflammatory approach. Here, we focus on accumulated evidence for a peculiar pharmacological profile of nimesulide., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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4. Adenosine signalling mediates the anti-inflammatory effects of the COX-2 inhibitor nimesulide.
- Author
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Caiazzo E, Maione F, Morello S, Lapucci A, Paccosi S, Steckel B, Lavecchia A, Parenti A, Iuvone T, Schrader J, Ialenti A, and Cicala C
- Subjects
- 5'-Nucleotidase antagonists & inhibitors, 5'-Nucleotidase blood, 5'-Nucleotidase metabolism, Animals, Anti-Inflammatory Agents therapeutic use, Cell Line, Cyclooxygenase 2 Inhibitors administration & dosage, Dinoprostone blood, Edema drug therapy, Edema immunology, Edema metabolism, Macrophages drug effects, Macrophages immunology, Male, Rats, Wistar, Receptor, Adenosine A2A metabolism, Sulfonamides administration & dosage, Adenosine metabolism, Anti-Inflammatory Agents pharmacology, Cyclooxygenase 2 Inhibitors pharmacology, Signal Transduction drug effects, Sulfonamides pharmacology
- Abstract
Extracellular adenosine formation from ATP is controlled by ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase/CD39) and ecto-5'-nucleotidase (e-5NT/CD73); the latter converts AMP to adenosine and inorganic phosphate, representing the rate limiting step controlling the ratio between extracellular ATP and adenosine. Evidence that cellular expression and activity of CD39 and CD73 may be subject to changes under pathophysiological conditions has identified this pathway as an endogenous modulator in several diseases and was shown to be involved in the molecular mechanism of drugs, such as methotrexate, salicylates , interferon-β. We evaluated whether CD73/adenosine/A2A signalling pathway is involved in nimesulide anti-inflammatory effect, in vivo and in vitro. We found that the adenosine A2A agonist, 4-[2-[[6-amino-9-(N-ethyl-β-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS21680, 2mg/kg ip.), inhibited carrageenan-induced rat paw oedema and the effect was reversed by co-administration of the A2A antagonist -(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM241385; 3mg/kg i.p.). Nimesulide (5mg/kg i.p.) anti-inflammatory effect was inhibited by pre-treatment with ZM241385 (3mg/kg i.p.) and by local administration of the CD73 inhibitor, adenosine 5'-(α,β-methylene)diphosphate (APCP; 400μg/paw). Furthermore, we found increased activity of 5'-nucleotidase/CD73 in paws and plasma of nimesulide treated rats, 4h following oedema induction. In vitro, the inhibitory effect of nimesulide on nitrite and prostaglandin E2 production by lipopolysaccharide-activated J774 cell line was reversed by ZM241385 and APCP. Furthermore, nimesulide increased CD73 activity in J774 macrophages while it did not inhibit nitrite accumulation by lipopolysaccharide-activated SiRNA CD73 silenced J774 macrophages. Our data demonstrate that the anti-inflammatory effect of nimesulide in part is mediated by CD73-derived adenosine acting on A2A receptors., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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5. Adenosine signaling in airways: toward a promising antiasthmatic approach.
- Author
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Cicala C and Ialenti A
- Subjects
- Animals, Anti-Asthmatic Agents therapeutic use, Asthma metabolism, Asthma pathology, Asthma therapy, Humans, Respiratory System drug effects, Adenosine metabolism, Anti-Asthmatic Agents pharmacology, Respiratory System metabolism, Respiratory System pathology, Signal Transduction drug effects
- Abstract
Adenosine participates to asthma physiopathology by signaling through more than just one receptor subtype. Defining the role of each receptor is complicated by evidence that often results obtained on rodents do not coincide with human studies, but what emerges is that an important condition to establish hyperresponsiveness to adenosine in any species of sensitized animals is the exposure to allergen; this feature appears to be very similar to the human situation, since allergic humans regularly undergo exposure to allergen. Furthermore, A₂B in humans, but A₃ receptor in rodents, would mediate, indirectly, the bronchoconstriction in response to adenosine and would play the main role in adenosine-induced airway inflammation and airway hyperreactivity. On the other hand, A₁ receptor over-expressed on asthmatic airways would mediate a direct adenosine bronchoconstrictor effect. Antagonists and agonists to adenosine receptors have been considered as antiasthmatic drugs but often their development has been limited by unwanted effects. Preventing adenosine accumulation in airways should be considered as a novel promising antiasthmatic strategy., (© 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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6. Hyperresponsiveness to adenosine in sensitized Wistar rats over-expressing A1 receptor.
- Author
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Alfieri A, Parisi A, Maione F, Grassia G, Morello S, Ialenti A, Mascolo N, and Cicala C
- Subjects
- Adenosine A1 Receptor Antagonists pharmacology, Allergens immunology, Animals, Bronchi drug effects, Bronchi immunology, Bronchi metabolism, Bronchi pathology, Edema immunology, Male, Ovalbumin immunology, Rats, Rats, Wistar, Time Factors, Adenosine pharmacology, Gene Expression Regulation drug effects, Gene Expression Regulation immunology, Hypersensitivity immunology, Hypersensitivity metabolism, Immunization, Receptor, Adenosine A1 metabolism
- Abstract
Airway hyperreactivity is characterized by increased responsiveness to bronchoconstrictor stimuli and it is hallmark of asthma. Adenosine is an ubiquitous signaling nucleoside resulting from ATP catabolism, whose extracellular levels increase following cellular damage or stress. Adenosine plays a role in asthma; asthmatics, but not normal subjects, present bronchoconstriction following inhalation of adenosine or of its precursor, adenosine-5'-monophosphate, most likely via adenosine A(2B) receptor on mast cells. However, the mechanism underling the increased airway smooth muscle sensitivity to adenosine in asthmatics remains to be elucidated. Early experimental studies suggested the involvement of A(1) receptor; this hypothesis has been confirmed by more recent studies on guinea pigs and is corroborated by the finding of an increased adenosine A(1) expression on asthmatic bronchial tissues. Brown Norway rats, the strain usually used to assess asthma models, develop hyperresponsiveness to adenosine 3h following allergen challenge, but not 24h thereafter, without involvement of A(1) receptor. Here, we investigated the role of adenosine A(1) receptor in sensitized Wistar rats showing airway hyperresponsiveness 24h following allergen challenge. We found that on bronchi of sensitized Wistar rats challenged with allergen there is an increased adenosine A(1) receptor expression on smooth muscle that is responsible for hyperresponsiveness to adenosine and ovalbumin., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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7. Inhibition of cyclooxygenase-2 gene expression by the heat shock response in J774 murine macrophages.
- Author
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Ialenti A, Di Meglio P, D'Acquisto F, Pisano B, Maffia P, Grassia G, Di Rosa M, and Ianaro A
- Subjects
- Animals, Blotting, Western, Cell Line, Cyclooxygenase 2, DNA-Binding Proteins metabolism, Dinoprostone biosynthesis, Electrophoretic Mobility Shift Assay, Gene Expression Regulation, Enzymologic drug effects, HSP72 Heat-Shock Proteins, Heat Shock Transcription Factors, Heat-Shock Proteins metabolism, Lipopolysaccharides pharmacology, Macrophages cytology, Macrophages drug effects, Mice, NF-kappa B metabolism, Protein Binding, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Heat-Shock Response physiology, Macrophages metabolism, Prostaglandin-Endoperoxide Synthases genetics
- Abstract
The heat shock response is a highly conserved mechanism of protection elicited in the cell by various kinds of stimuli, such as heat, sodium arsenite, oxidants and inflammation. Among the mechanisms potentially involved in mediating the protective effects of hsp, one of the most investigated is the inhibition of pro-inflammatory gene expression such as inducible nitric oxide synthase (iNOS) and inflammatory cytokines. Nevertheless, data about the effects of heat shock response on cyclooxygenase-2 expression in activated macrophages are so far not available in literature. The aim of this study was to investigate the changes in cyclooxygenase-2 expression following lipopolysaccharide stimulation of heat shocked J774 murine macrophages. We found, by Western blotting analysis and reverse transcription-polymerase chain reaction analysis (RT-PCR), that the lipopolysaccharide-induced cyclooxygenase-2 gene expression was reduced in heat shocked cells. Such a reduction was associated to activation of heat shock factor, increased levels of heat shock protein 72 and inhibition of lipopolysaccharide-induced nuclear factor-kappaB binding activity. These data suggest that the heat shock response inhibits cyclooxygenase-2 gene expression at transcriptional level, i.e. by preventing the activation of nuclear factor-kappaB, and provide additional information about mechanism(s) underlying the anti-inflammatory effect of the heat shock proteins.
- Published
- 2005
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8. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation.
- Author
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Cuzzocrea S, Pisano B, Dugo L, Ianaro A, Maffia P, Patel NS, Di Paola R, Ialenti A, Genovese T, Chatterjee PK, Di Rosa M, Caputi AP, and Thiemermann C
- Subjects
- Animals, Carrageenan, Cyclooxygenase 2, Cytokines biosynthesis, Dinoprostone metabolism, Edema chemically induced, Edema pathology, Edema prevention & control, Exudates and Transudates metabolism, Immunohistochemistry, Isoenzymes biosynthesis, Lipid Peroxidation drug effects, Lung pathology, Male, Neutrophil Infiltration drug effects, Nitrates metabolism, Nitric Oxide Synthase biosynthesis, Nitric Oxide Synthase Type II, Nitrites metabolism, Peroxidase metabolism, Pleurisy chemically induced, Pleurisy pathology, Pleurisy prevention & control, Poly(ADP-ribose) Polymerases metabolism, Prostaglandin-Endoperoxide Synthases biosynthesis, Rats, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, Rosiglitazone, Thiazolidinediones antagonists & inhibitors, Transcription Factors antagonists & inhibitors, Tyrosine metabolism, Anti-Inflammatory Agents, Receptors, Cytoplasmic and Nuclear agonists, Thiazolidinediones pharmacology, Transcription Factors agonists
- Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. The thiazolidinedione rosiglitazone (Avandia) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, that was recently approved by the Food and Drug Administration for treatment of type II diabetes mellitus. In the present study, we have investigated the effects of rosiglitazone in animal models of acute inflammation (carrageenan-induced paw oedema and carrageenan-induced pleurisy). We report here for the first time that rosiglitazone (given at 1, 3 or 10 mg/kg i.p. concomitantly with carrageenan injection in the paw oedema model, or at 3, 10 or 30 mg/kg i.p. 15 min before carrageenan administration in the pleurisy model) exerts potent anti-inflammatory effects (e.g. inhibition of paw oedema, pleural exudate formation, mononuclear cell infiltration and histological injury) in vivo. Furthermore, rosiglitazone reduced: (1) the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase (PARP), (2) the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), intercellular adhesion molecules-1 (ICAM-1) and P-selectin in the lungs of carrageenan-treated rats. In order to elucidate whether the protective effect of rosiglitazone is related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone. BADGE (30 mg/kg i.p.) administered 30 min prior to treatment with rosiglitazone significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the anti-inflammatory effects of rosiglitazone. We propose that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of inflammation.
- Published
- 2004
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