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1. Sex Hormone–Dependent Lipid Mediator Formation in Male and Female Mice During Peritonitis

Author

Troisi F., Pace S., Jordan P. M., Meyer K. P. L., Bilancia R., Ialenti A., Borrelli F., Rossi A., Sautebin L., Serhan C. N., Werz O., Troisi, F., Pace, S., Jordan, P. M., Meyer, K. P. L., Bilancia, R., Ialenti, A., Borrelli, F., Rossi, A., Sautebin, L., Serhan, C. N., and Werz, O.

Subjects
peritoniti, inflammation, specialized pro-resolving mediators, sex difference, lipid mediator, lipoxygenase
Abstract

Introduction: Sex differences in inflammation are obvious and contribute to divergences in the incidence and severity of inflammation-related diseases that frequently preponderate in women. Lipid mediators (LMs), mainly produced by lipoxygenase (LOX) and cyclooxygenase (COX) pathways from polyunsaturated fatty acids (PUFAs), regulate all stages of inflammation. Experimental and clinical studies revealed sex divergences for selected LM pathways without covering the entire LM spectrum, and only few studies have addressed the respective role of sex hormones. Here, we performed the comprehensive LM profile analysis with inflammatory peritoneal exudates and plasma from male and female mice in zymosan-induced peritonitis to identify the potential sex differences in LM biosynthesis during the inflammatory response. We also addressed the impact of sex hormones by employing gonadectomy. Methods: Adult male and female CD1 mice received intraperitoneal injection of zymosan to induce peritonitis, a well-established experimental model of acute, self-resolving inflammation. Mice were gonadectomized 5 weeks prior to peritonitis induction. Peritoneal exudates and plasma were taken at 4 (peak of inflammation) and 24 h (onset of resolution) post zymosan and subjected to UPLC–MS-MS–based LM signature profiling; exudates were analyzed for LM biosynthetic proteins by Western blot; and plasma was analyzed for cytokines by ELISA. Results: Pro-inflammatory COX and 5-LOX products predominated in the peritoneum of males at 4 and 24 h post-zymosan, respectively, with slightly higher 12/15-LOX products in males after 24 h. Amounts of COX-2, 5-LOX/FLAP, and 15-LOX-1 were similar in exudates of males and females. In plasma of males, only moderate elevation of these LMs was apparent. At 4 h post-zymosan, gonadectomy strongly elevated 12/15-LOX products in the exudates of males, while in females, free PUFA and LOX products were rather impaired. In plasma, gonadectomy impaired most LMs in both sexes at 4 h with rather up-regulatory effects at 24 h. Finally, elevated 15-LOX-1 protein was evident in exudates of males at 24 h which was impaired by orchiectomy without the striking impact of gonadectomy on other enzymes in both sexes. Conclusions: Our results reveal obvious sex differences and roles of sex hormones in LM biosynthetic networks in acute self-resolving inflammation in mice, with several preponderances in males that appear under the control of androgens.

Published
2022

2. The novel anti-inflammatory agent VA694, endowed with both NO-releasing and COX2-selective inhibiting properties, exhibits NO-mediated positive effects on blood pressure, coronary flow and endothelium in an experimental model of hypertension and endothelial dysfunction

Author

Martelli, A., Testai, L., Anzini, M., Cappelli, A., Di Capua, A., Biava, M., Poce, G., Consalvi, S., Giordani, A., Caselli, G., Rovati, L., Ghelardini, C., Patrignani, P., Sautebin, L., Breschi, M.C., and Calderone, V.

Published
2013
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14. Evaluation of Dual 5-Lipoxygenase/Microsomal Prostaglandin E2 Synthase-1 Inhibitory Effect of Natural and Synthetic Acronychia-Type Isoprenylated Acetophenones

Author

Svouraki, A. Garscha, U. Kouloura, E. Pace, S. Pergola, C. Krauth, V. Rossi, A. Sautebin, L. Halabalaki, M. Werz, O. Gaboriaud-Kolar, N. Skaltsounis, A.-L.

Abstract

Among the pathways responsible for the development of inflammatory responses, the cyclooxygenase and lipoxygenase pathways are among the most important ones. Two key enzymes, namely, 5-LO and mPGES-1, are involved in the biosynthesis of leukotrienes and prostaglandins, respectively, which are considered attractive therapeutic targets, so their dual inhibition might be an effective strategy to control inflammatory deregulation. Several natural products have been identified as 5-LO inhibitors, with some also being dual 5-LO/mPGES-1 inhibitors. Here, some prenylated acetophenone dimers from Acronychia pedunculata have been identified for their dual inhibitory potency toward 5-LO and mPGES-1. To gain insight into the SAR of this family of natural products, the synthesis and biological evaluation of analogues are presented. The results show the ability of the natural and synthetic molecules to potently inhibit 5-LO and mPEGS-1 in vitro. The potency of the most active compound (10) has been evaluated in vivo in an acute inflammatory mouse model and displayed potent anti-inflammatory activity comparable in potency to the drug zileuton used as a positive control. © 2017 The American Chemical Society and American Society of Pharmacognosy.

Published
2017

15. Poster Presentations

Author

Polimeni, G., Russo, A., Catania, M. A., Trifirò, G., Cupani, C., Oteri, A., Fava, G., Alacqua, M., Gentile, M., Rossi, A., Aiello, A., Iacobelli, M., Sautebin, L., Calapai, G., and Caputi, A. P.

Published
2007
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24. Myrtucommulone from Myrtus communis exhibits potent anti-inflammatory effectiveness in vivo

Author

Rossi, A, Di Paola, R, Mazzon, E, Genovese, Tiziana, Caminiti, Rocco, Bramanti, Placido, Pergola, C, Koeberle, A, Werz, O, Sautebin, L, Cuzzocrea, Salvatore, DI PAOLA, Rosanna, Rossi, Antonietta, DI PAOLA, R., Mazzon, E., Genovese, T., Caminiti, R., Bramanti, P., Pergola, C., Koeberle, A., Werz, O., Sautebin, Lidia, and Cuzzocrea, S.

Subjects
Male, Pathology, medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, Blotting, Western, Interleukin-1beta, Lung injury, Pharmacology, Biology, Phloroglucinol, Carrageenan, Leukotriene B4, Thiobarbituric Acid Reactive Substances, Anti-inflammatory, Dinoprostone, Proinflammatory cytokine, chemistry.chemical_compound, Mice, In vivo, medicine, Animals, Edema, carrageenan edema, Pleurisy, Peroxidase, Myrtus communis, Myrtucommulone, Foot, Tumor Necrosis Factor-alpha, Nitrotyrosine, Anti-Inflammatory Agents, Non-Steroidal, anti-inflammatory effectivene, Intercellular Adhesion Molecule-1, Immunohistochemistry, Myrtus, P-Selectin, chemistry, Cyclooxygenase 2, carrageenan pleurisy, Myrtus communi, Molecular Medicine, Cytokines, Lipid Peroxidation, Prostaglandin E
Abstract

Myrtucommulone a nonprenylated acylphloroglucinol contained in the leaves of myrtle (Myrtus communis), has been reported to suppress the biosynthesis of eicosanoids by inhibition of 5-lipoxygenase and cyclooxygenase-1 in vitro and to inhibit the release of elastase and the formation of reactive oxygen species in activated polymorphonuclear leukocytes. Here, in view of the ability of MC to suppress typical proinflammatory cellular responses in vitro, we have investigated the effects of MC in in vivo models of inflammation. MC was administered to mice intraperitoneally, and paw edema and pleurisy were induced by the subplantar and intrapleural injection of carrageenan, respectively. MC (0.5, 1.5, and 4.5 mg/kg i.p.) reduced the development of mouse carrageenan-induced paw edema in a dose-dependent manner. Moreover, MC (4.5 mg/kg i.p. 30 min before and after carrageenan) exerted anti-inflammatory effects in the pleurisy model. In particular, 4 h after carrageenan injection in the pleurisy model, MC reduced: 1) the exudate volume and leukocyte numbers; 2) lung injury (histological analysis) and neutrophil infiltration (myeloperoxidase activity); 3) the lung intercellular adhesion molecule-1 and P-selectin immunohistochemical localization; 4) the cytokine levels (tumor necrosis factor-α and interleukin-1 β in the pleural exudate and their immunohistochemical localization in the lung; 5) the leukotriene B 4, but not prostaglandin E2, levels in the pleural exudates; and 6) lung peroxidation (thiobarbituric acid-reactant substance) and nitrotyrosine and poly (ADP-ribose) immunostaining. In conclusion, our results demonstrate that MC exerts potent anti-inflammatory effects in vivo and offer a novel therapeutic approach for the management of acute inflammation. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.

Published
2009

29. PROTECTIVE EFFECTS OF ANTHOCYANINS FROM BLACKBERRY IN A RAT MODEL OF ACUTE LUNG INFLAMMATION

Author

Rossi, A, Serraino, I, Dugo, Paola, DI PAOLA, R, Mondello, Luigi, Genovese, Tiziana, Morabito, D, Dugo, Giovanni, Sautebin, L, Caputi, Achille, Cuzzocrea, Salvatore, DI PAOLA, Rosanna, Rossi, Antonietta, Serraino, I., Dugo, P., DI PAOLA, R., Mondello, L., Genovese, T., Morabito, D., Dugo, G., Sautebin, Lidia, Caputi, A. P., and Cuzzocrea, S.

Subjects
Male, Time Factors, Neutrophils, Rat model, Inflammation, Carrageenan, Biochemistry, Dinoprostone, Lipid peroxidation, Anthocyanins, Rats, Sprague-Dawley, Pigment, chemistry.chemical_compound, Glucosides, Malondialdehyde, medicine, Animals, Food science, Lung, Pleurisy, Tyrosine Metabolism, Nitrites, Peroxidase, Nitrates, Plant Extracts, fungi, food and beverages, General Medicine, Exudates and Transudates, Intercellular Adhesion Molecule-1, Immunohistochemistry, Rats, Sprague dawley, medicine.anatomical_structure, chemistry, visual_art, Fruit, Acute Disease, visual_art.visual_art_medium, Tyrosine, Lipid Peroxidation, Anthocyanins, Blackberry, Carrageenan, Inflammation, Pleurisy, medicine.symptom, Poly(ADP-ribose) Polymerases
Abstract

Anthocyanins are a group of naturally occuring phenolic compounds related to the coloring of plants, flowers and fruits. These pigments are important as quality indicators, as chemotaxonomic markers and for their antioxidant activities. Here, we have investigated the therapeutic efficacy of anthocyanins contained in blackberry extract (cyanidin-3-O-glucoside represents about 80% of the total anthocyanin contents) in an experimental model of lung inflammation induced by carrageenan in rats. Injection of carrageenan into the pleural cavity elicited an acute inflammatory response characterized by fluid accumulation which contained a large number of neutrophils as well as an infiltration of polymorphonuclear leukocytes in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx) and prostaglandin E2 (PGE2). All parameters of inflammation were attenuated in a dose-dependent manner by anthocyanins (10, 30 mg kg(-1) 30 min before carrageenan). Furthermore, carrageenan induced an upregulation of the adhesion molecule ICAM-1, nitrotyrosine and poly (ADP-ribose) synthetase (PARS) as determined by immunohistochemical analysis of lung tissues. The degree of staining was lowered by anthocyanins treatment. Thus, the anthocyanins contained in the blackberry extract exert multiple protective effects in carrageenan-induced pleurisy.

Published
2003

30. 17 beta-estradiol antiinflammatory activity in carrageenan- induced pleurisy

Author

Cuzzocrea, Salvatore, Santagati, S, Sautebin, L, Mazzon, E, Calabro, G, Serraino, I, Caputi, Achille, and Maggi, A.

Subjects
ESTROGEN, INFLAMMATION, NITRIC-OXIDE SYNTHASE, ADP-RIBOSE SYNTHETASE, SEX-HORMONES, RHEUMATOID-ARTHRITIS, INDUCED MODELS, PAW EDEMA, PEROXYNITRITE, RAT
Published
2000

31. Effects of intracerebroventricular leptin administration on food intake, body weight gain and diencephalic nitric oxide synthase activity in the mouse

Author

Calapai, Gioacchino, Corica, Francesco, Allegra, Alessandro, Corsonello, A, Sautebin, L, De Gregorio, T, Di Rosa, M, Costantino, G, Buemi, Michele, Caputi, Achille, Calapai, G., Corica, F., Allegra, A., Corsonello, A., Sautebin, Lidia, DE GREGORIO, T., DI ROSA, M., Costantino, G., Buemi, M., and Caputi, A. P.

Subjects
Leptin, Male, Time Factors, digestive, oral, and skin physiology, Body Weight, Brain, Proteins, Arginine, nitric oxide, L-arginine, food intake, body weight gain, brain, obesity, Eating, Mice, Papers, Animals, Drug Interactions, Obesity, Diencephalon, Nitric Oxide Synthase, Injections, Intraventricular
Abstract

1. Intracranial administration of leptin reduces both food intake and body weight gain in the mouse. Inhibitors of nitric oxide (NO) synthase produce similar effects. 2. To investigate the role of the brain L-arginine/NO pathway in mediating this effect of leptin, we have evaluated food intake and body weight gain after daily (5 days) intracerebroventricular (i.c.v.) administration of leptin (0.5-2 microg) alone or in association with L-arginine (10 microg). Moreover, we measured diencephalic nitric oxide synthase (NOS) activity after a single i.c.v. leptin (0.25-2 microg) injection and after consecutive doses of leptin (0.25-2 microg) over 5 days. The time course of the effect of leptin on NOS activity was also evaluated. 3. I.c.v. injected leptin (1 and 2 microg) significantly and dose-dependently reduced food intake and body weight gain with respect to vehicle (food intake: 5.97+/-0.16 g 24 h(-1) and 4.27+/-0.18 g 24 h(-1), respectively, vs 8.05+/-0.34 g 24 h(-1), P0.001, n=6 for each group; body weight gain: -10.7+/-0.46% and -15.7+/-0.65%, respectively, vs 5.14+/-0.38%, P0.001, n=6 for each group). This effect was antagonized by L-arginine (food intake: 7.90+/-0.37 g 24 h; body weight gain: 5.11+/-0.31%, n=6). Diencephalic NOS activity was significantly reduced by the highest doses of leptin with respect to vehicle (vehicle: 0.90+/-0.04 nmol citrulline min(-1) g(-1) tissue; leptin 1 microg: 0.62+/-0.03 nmol citrulline min(-1) g(-1) tissue, P0.001; leptin 2 microg: 0.44+/-0.03 nmol citrulline min(-1) g(-1) tissue, P0.001, n=6 for each group). Similar results were obtained in animals treated with daily consecutive doses of leptin. The inhibitory effect appeared rapidly (within 30 min) and was long lasting (up to 12 h). 4. Our results suggest that the brain L-arginine/NO pathway may be involved in the central effect of leptin on feeding behaviour and body weight gain in mice.

Published
1998

32. The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages.

Author

Rossi, A, Pergola, C, Koeberle, A, Hoffmann, M, Dehm, F, Bramanti, P, Cuzzocrea, S, Werz, O, and Sautebin, L

Subjects
LIPOXYGENASES, ENZYME inhibitors, PROSTAGLANDIN synthesis, ARACHIDONIC acid, MACROPHAGES, ASTHMA treatment, LABORATORY mice, CYCLOOXYGENASE 2, GENE expression
Abstract

Background and Purpose: Zileuton is the only 5-lipoxygenase (5-LOX) inhibitor marketed as a treatment for asthma, and is often utilized as a selective tool to evaluate the role of 5-LOX and leukotrienes. The aim of this study was to investigate the effect of zileuton on prostaglandin (PG) production in vitro and in vivo.Experimental Approach: Peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon γ (LPS/IFNγ), J774 macrophages and human whole blood stimulated with LPS were used as in vitro models and rat carrageenan-induced pleurisy as an in vivo model.Key Results: Zileuton suppressed PG biosynthesis by interference with arachidonic acid (AA) release in macrophages. We found that zileuton significantly reduced PGE2 and 6-keto prostaglandin F1α (PGF1α) levels in activated mouse peritoneal macrophages and in J774 macrophages. This effect was not related to 5-LOX inhibition, because it was also observed in macrophages from 5-LOX knockout mice. Notably, zileuton inhibited PGE2 production in LPS-stimulated human whole blood and suppressed PGE2 and 6-keto PGF1α pleural levels in rat carrageenan-induced pleurisy. Interestingly, zileuton failed to inhibit the activity of microsomal PGE2 synthase1 and of cyclooxygenase (COX)-2 and did not affect COX-2 expression. However, zileuton significantly decreased AA release in macrophages accompanied by inhibition of phospholipase A2 translocation to cellular membranes.Conclusions and Implication: Zileuton inhibited PG production by interfering at the level of AA release. Its mechanism of action, as well as its use as a pharmacological tool, in experimental models of inflammation should be reassessed. [ABSTRACT FROM AUTHOR]

Published
2010
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33. Drug safety information through the internet: the experience of an Italian website.

Author

Polimeni G, Russo A, Catania MA, Aiello A, Oteri A, Trifirò G, Calapai G, Sautebin L, Iacobelli M, Caputi AP, Polimeni, Giovanni, Russo, Alessandra, Catania, Maria Antonietta, Aiello, Andrea, Oteri, Alessandro, Trifirò, Gianluca, Calapai, Gioacchino, Sautebin, Lidia, Iacobelli, Massimo, and Caputi, Achille P

Abstract

Background: The Internet may play a crucial role in the prompt provision of updated drug safety information. Nevertheless, limited knowledge of the English language among healthcare professionals or suboptimal search skills constitute barriers to widespread and appropriate use of the Internet for this purpose in Italy. In order to provide accurate information on drug safety and to promote the reporting of adverse drug reactions, in 1999 the clinical section of the Italian Society of Pharmacology created the website www.farmacovigilanza.org, financially supported by a non-profit foundation. The website promptly and independently provides news published in the international literature on drug safety, translated into Italian. The site also contains specific sections dedicated to adverse reactions to herbal products and cosmetic preparations.Objectives: The aim of this paper was to describe the number and characteristics of users and the most intensively visited sections of the website. Furthermore, in September 2006, 300 registered users who had accessed a registered users area aimed specifically at health professionals more than 20 times in the preceding 12 months received a ten-item multiple choice questionnaire via e-mail, to assess satisfaction with the accuracy and promptness of information provided, text comprehension and other information sources for drug-related issues. We hereby describe the results of the survey, after careful analysis of the questionnaires.Results: Up until July 2007, the site had over 600 000 direct accesses and 9760 healthcare professionals registered to use the site. A total of 108 responses to the e-mailed questionnaire were received (response rate = 36%), of which 103 were analysed; five were excluded due to missing information. Overall, the majority of responders judged the information on the site as objective and understandable. More than 85% of participants declared that the site has influenced their opinion and attitudes toward the safety of medicines. In particular, responders said that they pay more attention to drug interactions and to the safety profile of newly marketed drugs, and spend more time on communicating the risks of drugs used by their patients. Specifically, responders stated that they pay more attention to drug interactions (87.7%), newly marketed drugs (68.5%), herbal remedies (56.2%), drugs in patients at increased risk (42.5%), drugs in pregnant women (42.5%) and cosmetics (13.7%).Conclusions: The website www.farmacovigilanza.org appears to be an effective tool that provides users of the site with independent, relevant and reliable safety information. It was found to influence (and possibly improve) the quality of prescribing of a large proportion of the general practitioners who responded to our questionnaire, and our results indicate a high appreciation of the information found on the website. Moreover, the survey disclosed that there is a substantial need for such information in the national language by healthcare professionals. We think that our approach can serve as a model for similar initiatives in countries elsewhere in the world. [ABSTRACT FROM AUTHOR]

Published
2009
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34. Understanding the adverse effects of cosmetics: a pilot project in cosmetovigilance.

Author

Sautebin L and Sautebin, Lidia

Abstract

Currently, cosmetics and toiletries are very popular and their use continues to increase because consumers consider physical appearance important and, at the same time, these products are considered to be safe. However, in spite of their safety and tolerability, during recent decades, we have become aware that adverse effects can occur. The number of adverse effects known so far is very low indeed. This is partly because such adverse effects are underestimated as a result of self-diagnosis and self-medication, which are common behaviours in the presence of mild-to-moderate reactions, as in the case of cosmetics. Moreover, such effects are underestimated because of the absence of formal and reliable monitoring systems ('cosmetovigilance'). This requires the creation of a standard reporting form, as well as resolution concerning professional categories authorized to report and the subsequent validation/evaluation of the collected forms. All these items are of great importance, not only to investigate but also to prevent risks caused by cosmetic use. A pilot project was undertaken to test the effectiveness of a notification system by the validation of either a reporting form or the role of dermatologists and community pharmacists as reporting categories. Collection of reporting forms began in July 2006 and it is still in progress; the preliminary data reported here refer to the period July 2006-June 2007 and mainly concern the recording and validation of the collected reporting forms. During this period, we have received 40 reporting forms (32 by dermatologists and 8 by pharmacists). The validation process of the recorded forms revealed several drawbacks, such as incompleteness (19 forms), inadequacy of the description of the suspected undesirable effect and its location (2), illegible handwriting (6) and mistaken statements (3). Six forms reported a misuse of a cosmetic product: four of these were related to the site of application while two were related to time. In one case, instructions for use were not followed. In conclusion, our experience regarding the notification of adverse effects of cosmetics, although limited to a restricted geographical area, suggests that for an efficient and reliable monitoring system to be in place, which includes all the necessary measures to protect public health, an education and training programme for all stakeholders (health professionals, consumers and appropriate authorities) is required. [ABSTRACT FROM AUTHOR]

Published
2008
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35. Cyclooxygenase-2-dependent generation of 8-epiprostaglandin F2α by lipopolysaccharide-activated J774 macrophages.

Author

Sautebin, L., Ianaro, A., Rombolà, L., Ialenti, A., Sala, A., and Di Rosa, M.

Abstract

Objective: The generation of 8-epiprostaglandin F2α (8-epi-PGF2α) by arachidonic acid (AA)- and lipopolysaccharide (LPS)- stimulated J774 macrophages has been investigated.¶ Material: Murine monocyte/macrophage J774 cell line.¶ Methods: Cells were incubated with AA or LPS and the amount of 8-epi-PGF2α, 6-ketoprostaglandin F1α (6-keto-PGF1α) and prostaglandin E2 (PGE2) released in the incubation media measured by radioimmunoassay (RIA) or, in some experiments, by enzyme immunoassay (EIA). The effect of dexamethasone (DXM), cycloheximide (CXM) and 5,5 dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 (COX-2) selective inhibitor, on LPS-induced generation of AA metabolites was assessed.¶ Results: AA induced a significant production of 6-keto-PGF1α and PGE2, whereas LPS caused a concentration- and time-dependent increase of 8-epi-PGF2α, 6-keto-PGF1α and PGE2. DXM (2 μM) as well as CXM (1 μM) significantly decreased (p < 0.001; n = 4) the LPS-stimulated production of 8-epi-PGF2α (by 86% and 82%, respectively), 6-keto-PGF1α (by 78% and 74%, respectively) and PGE2 (by 83% and 78%, respectively). Immunostimulated production of AA metabolites was also inhibited by DFU (IC50 0.3 ± 0.04 μM; 0.16 ± 0.02 μM and 0.11 ± 0.05 μM for 8-epi-PGF2α, 6-keto-PGF1α and PGE2, respectively.¶ Conclusions: These results demonstrate the role of COX-2 in the generation of 8-epi-PGF2α by LPS-stimulated J774 macrophages. The relevance of these findings requires further elucidation. [ABSTRACT FROM AUTHOR]

Published
1999
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