Involvement of leukotriene pathway in the pathogenesis of ischemia-reperfusion injury and septic and non-septic shock.

The 5-lipoxygenase (5-LO) pathway is responsible for the production of leukotrienes (LTs), inflammatory lipid mediators which play a role in innate immunity. More recently, a pivotal role of LTs in ischemia-reperfusion and shock injury has been suggested. In fact, these pathological conditions are characterized by a severe neutrophil infiltration that gives rise to tissue injury and 5-LO metabolites control neutrophil recruitment in injured tissue by the modulation of adhesion molecule expression. The aim of this review is to analyze the results reported in the literature on the role of 5-LO pathway, with particular regard to LTs, in these pathological conditions. A better understanding of the mechanisms underlying the role of the 5-LO enzyme and/or its metabolites in the regulation of neutrophil trafficking, might open new perspectives in the therapy of organ dysfunction and/or injury associated with shock and ischemia-reperfusion injury

Inhibition of nitric oxide biosynthesis by anthocyanin fraction of blackberry extract.

Anthocyanins are natural colorant belonging to the flavonoid family, widely distributed among flowers, fruits, and vegetables. Some flavonoids have been found to possess anticarcinogenic, cytotoxic, cytostatic, antioxidant, and anti-inflammatory properties. Since increased nitric oxide (NO) plays a role in inflammation, we have investigated whether the pharmacological activity of the anthocyanin fraction of a blackberry extract (cyanidin-3-O-glucoside representing about 88% of the total anthocyanin content) was due to the suppression of NO synthesis. The markedly increased production of nitrites by stimulation of J774 cells with lipopolysaccharide (LPS) for 24 h was concentration-dependently inhibited by the anthocyanin fraction (11, 22, 45, and 90 μg/ml) of the extract. Moreover, this inhibition was dependent on a dual mechanism, since the extract attenuated iNOS protein expression and decreased the iNOS activity in lungs from LPS-stimulated rats. Inhibition of iNOS protein expression appeared to be at the transcriptional level, since the extract and similarly cyanidin-3-O-glucoside (10, 20, 40, and 80 μg/ml, amounts corresponding to the concentrations present in the extract) decreased LPS-induced NF-κB activation, through inhibition of IκBα degradation, and reduced ERK-1/2 phosphorylation in a concentration-dependent manner. In conclusion, our study demonstrates that at least some part of the anti-inflammatory activity of blackberry extract is due to the suppression of NO production by cyanidin-3-O-glucoside, which is the main anthocyanin present in the extract. The mechanism of this inhibition seems to be due to an action on the expression/activity of the enzyme. In particular, the protein expression was inhibited through the attenuation of NF-κB and/or MAPK activatio

THE INHIBITORY EFFECT OF PROPOLIS AND CAFFEIC ACID PHENETHYLESTER ON CYCLOOXYGENASE ACTIVITY IN J774 MACROPHAGES.

The effect of an ethanolic extract of propolis, with and without CAPE, and some of its components on cyclooxygenase (COX-1 and COX-2) activity in J774 macrophages has been investigated. COX-1 and COX-2 activity, measaured as prostaglandin E-2 (PGE(2)) production, were concentration-dependently inhibited by propolis (C x 10(-3)-3 x 10(2) mugml(-1)) with an IC50 of 2.7 mugml(-1) and 4.8 x 10(-2) mugml(-1), respectively. Among the compounds tested pinocembrin and caffeic, ferulic, cinnamic and chlorogenic acids did not affect the activity of COX isoforms. Conversely, CAPE (2.8 x 10(-4)-28 mugml(-1); 10(-9)-10(-4) M) and galangin (2.7 x 10(-4)-27 mugml(-1); 10(-9)-10(-4) M) were effective, the last being about ten-twenty times less potent. In fact the IC50 of CAPE for COX-1 and COX-2 were 4.4 x 10(-1) mugml(-1) (1.5 x 10(-6) M) and 2 x 10(-3) mugml(-1) (6.3 x 10(-9) M), respectively. The IC50 of galangin were 3.7 mugml(-1) (15 x 10(-6) M) and 3 x 10(-2) mugml(-1) (120 x 10(-1) M), for COX-1 and COX-2 respectively. To better investigate the role of CAPE, we tested the action of the ethanolic extract of propolis deprived of CAPE, which resulted about ten times less potent than the extract with CAPE in the inhibition of both COX-1 and COX-2, with an IC50 of 30 mugml(-1) and 5.3 x 10(-1) mugml(-1), respectively. Moreover the comparison of the inhibition curves showed a significant difference (p < 0.001). These results suggest that both CAPE and galangin contribute to the overall activity of propolis, CAPE being more effective

Inhibition of inducible Nitric Oxide Synthase expression by an acetonic extract from Feijoa sellowiana Berg. fruits.

Feijoa sellowiana Berg. fruits and especially the acetonic extract have been shown to possess biological activities, although the responsible compounds have never been identified. The present study was designed to evaluate the anti-inflammatory activity of an acetonic extract from F. sellowiana Berg. fruits on the nitric oxide (NO) pathway, which plays an important role in inflammation. To this aim the J774 cell line, which expresses inducible nitric oxide synthase (iNOS) following stimulation with lipopolysaccharide (LPS), has been utilized, and the effects of this extract and its fractions on NO production, iNOS protein expression, and signal pathways involved in its regulation have been evaluated. This study demonstrates that at least some part of the anti-inflammatory activity of the acetonic extract is due to the suppression of NO production by flavone and stearic acid. The mechanism of this inhibition seems to be related to an action on the expression of the enzyme iNOS through the attenuation of nuclear factor κB (NF-κB) and/or mitogen-activated protein kinase (MAPK) activation

The Role of 5-Lipoxygenase and Leukotrienes in Shock and Ischemia-Reperfusion Injury

The leukotrienes (LTs) are metabolic products of arachidonic acid via the 5-lipoxygenase (5-LO) pathway. The biological activities of LTs suggest that they are mediators of acute inflammatory and immediate hypersensitivity responses. In particular, the 5-LO activation has been proposed to be an important regulator for pathogenesis in multicellular organisms. The role of LTs in tissue damage, associated with septic and nonseptic shock and ischemia-reperfusion, has been extensively studied by the use of 5-LO inhibitors, receptor antagonists, and mice with a targeted disruption of the 5-LO gene (5-LOKO). In particular, several data indicate that LTs regulate neutrophil trafficking in damaged tissue in shock and ischemia-reperfusion, mainly through the modulation of adhesion molecule expression. This concept may provide new insights into the interpretation of the protective effect of 5-LO inhibition, which may be useful in the therapy of pathological conditions associated with septic and nonseptic shock and ischemia-reperfusion injury

La campagna iberista nella rivista modernista portoghese Contemporânea (1922-1926)

This work aims to analyse the role that the modernist magazine Contemporânea played in popularizing Iberian theories in the Lusitanian area, between 1922 and 1926, to promote an economic revival and an intercultural exchange between Spain and Portugal, which suffered a setback after the end of the Iberian Union (1580-1640). In the context of the “Iberian Studies”, this work proposes the textual analysis of the articles that contribute to the diffusion of Iberian doctrines to re-establish the transnational dialogue between the two areas and to resolve, mostly, the state of general decline.Il presente lavoro analizza il ruolo che la rivista modernista Contemporânea ha svolto nel divulgare le teorie iberiche nell’area lusitana, tra il 1922 e il 1926, per promuovere la ripresa economica e lo scambio interculturale tra Spagna e Portogallo, che ha subito un drastico arresto dopo la fine dell’Unione Iberica (1580-1640). Nell’ambito degli Studi Iberici, il saggio propone l’analisi testuale degli articoli che contribuiscono alla diffusione delle dottrine iberiche per ristabilire il dialogo transnazionale tra i due Paesi e per risolvere, soprattutto, lo stato di generale declino

Didática inclusiva do Português como Língua Estrangeira. Estratégias para estudantes italofalantes com Necessidades Educativas Especiais (NEE)

Considering the current academic context, which is increasingly heterogeneous due to the presence of students from different sociocultural backgrounds with Special Educational Needs (SEN), in particular with Specific Learning Disorders (LSD), this article aims to discuss and propose inclusive teaching methodologies to be used in order to promote an effective teaching of Portuguese as a Foreign Language for Italian-speaking students with Dysgraphia and Dyslexia, a still virgin head of study in the field of Lusitanian Linguistics. In addition, we will also analyze compensatory and dispensatory instruments, recommended by ministerial directives, to be used to promote the Meaningful Learning in the target language within an emotionally propitious environment that reduces the Affective Filter, responsible for the activation of high levels of linguistic anxiety that block the internalization of notions and lexical units in the encyclopedic memory of the students in question

Arzanol, a prenylated heterodimeric phloroglucinyl pyrone, inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy in vivo.

Based on its capacity to inhibit in vitro HIV-1 replication in T cells and the release of pro-inflammatory cytokines in monocytes, the prenylated heterodimeric phloroglucinyl α-pyrone arzanol was identified as the major anti-inflammatory and anti-viral constituent from Helichrysum italicum. We have now investigated the activity of arzanol on the biosynthesis of pro-inflammatory eicosanoids, evaluating its anti-inflammatory efficacy in vitro and in vivo. Arzanol inhibited 5-lipoxygenase (EC 7.13.11.34) activity and related leukotriene formation in neutrophils, as well as the activity of cyclooxygenase (COX)-1 (EC 1.14.99.1) and the formation of COX-2-derived prostaglandin (PG)E(2)in vitro (IC(50)=2.3-9μM). Detailed studies revealed that arzanol primarily inhibits microsomal PGE(2) synthase (mPGES)-1 (EC 5.3.99.3, IC(50)=0.4μM) rather than COX-2. In fact, arzanol could block COX-2/mPGES-1-mediated PGE(2) biosynthesis in lipopolysaccharide-stimulated human monocytes and human whole blood, but not the concomitant COX-2-derived biosynthesis of thromboxane B(2) or of 6-keto PGF(1α), and the expression of COX-2 or mPGES-1 protein was not affected. Arzanol potently suppressed the inflammatory response of the carrageenan-induced pleurisy in rats (3.6mg/kg, i.p.), with significantly reduced levels of PGE(2) in the pleural exudates. Taken together, our data show that arzanol potently inhibits the biosynthesis of pro-inflammatory lipid mediators like PGE(2)in vitro and in vivo, providing a mechanistic rationale for the anti-inflammatory activity of H. italicum, and a rationale for further pre-clinical evaluation of this novel anti-inflammatory lead

Structural optimization and biological evaluation of 2-substituted 5-hydroxyindole-3-carboxylates as potent inhibitors of human 5-lipoxygenase.

Pharmacological suppression of leukotriene biosynthesis by inhibitors of 5-lipoxygenase (5-LO) is a strategy to intervene with inflammatory and allergic disorders. We recently presented 2-amino-5-hydroxy-1H-indoles as efficient 5-LO inhibitors in cell-based and cell-free assays. Structural optimization led to novel benzo[g]indole-3-carboxylates exemplified by ethyl 2-(3-chlorobenzyl)-5- hydroxy-1H-benzo[g]indole-3-carboxylate (compound 11a), which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC50 values of 0.23 and 0.086 μM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC50 = 0.83-1.6 μM) and significantly prevented leukotriene B4 production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3-carboxylates may have potential as anti-inflammatory therapeutics

Lung ultrasound in systemic sclerosis: correlation with high-resolution computed tomography, pulmonary function tests and clinical variables of disease

Interstitial lung disease (ILD) is a hallmark of systemic sclerosis (SSc). Although high-resolution computed tomography (HRCT) is the gold standard to diagnose ILD, recently lung ultrasound (LUS) has emerged in SSc patients as a new promising technique for the ILD evaluation, noninvasive and radiation-free. The aim of this study was to evaluate if there is a correlation between LUS, chest HRCT, pulmonary function tests findings and clinical variables of the disease. Thirty-nine patients (33 women and 6 men; mean age 51 ± 15.2 years) underwent clinical examination, HRCT, pulmonary function tests and LUS for detection of B-lines. A positive correlation exists between the number of B-lines and the HRCT score (r = 0.81, p &lt; 0.0001), conversely a negative correlation exists between the number of B-lines and diffusing capacity of the lung for carbon monoxide (DLCO) (r = −0.63, p &lt; 0.0001). The number of B-lines increases along with the progression of the capillaroscopic damage. A statistically significant difference in the number of B-lines was found between patients with and without digital ulcers [42 (3–84) vs 16 (4–55)]. We found that the number of B-lines increased with the progression of both HRCT score and digital vascular damage. LUS may therefore, be a useful tool to determine the best timing for HRCT execution, thus, preventing for many patients a continuous and useless exposure to ionizing radiatio