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Biomedical subjects

Alfredo Vannacci

Publications and source records attributed to Alfredo Vannacci.

At least 19 recordsLinked to original sources
PubMed2006

Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists.

On the basis of docking studies carried out using the recently published cannabinoid receptor models,35 new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, which presented p-fluorobenzyl and carboxycycloheptylamide substituents bound in the 1 and 3 positions of the 1,8-naphthyiridine-4-one nucleus, showed a high CB2 affinity with a Ki of 1.0 nM. The substitution of the naphthyridine-4-one nucleus with the quinoline-4-one system determined a general increase in CB2 affinity. In particular, the N-cyclohexyl-7-chloro-1-(2-morpholin-4-ylethyl)quinolin-4(1H)-on-3-carboxamide (40) possessed a remarkable affinity, with Ki of 3.3 nM, which was also accompanied by a high selectivity for the CB2 receptor (Ki(CB1)/Ki(CB2) ratio greater than 303). Moreover, the [35S]GTPgamma binding assay and functional studies on human basophils indicated that the 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives behaved as CB1 and CB2 receptor agonists.

Amides↗
PubMed2006

Protective effects of relaxin in ischemia/reperfusion-induced intestinal injury due to splanchnic artery occlusion.

1. Splanchnic artery occlusion (SAO) followed by reperfusion causes endothelial injury and inflammation which contribute to the pathophysiology of shock. We investigated the effects of relaxin (RLX), known to afford protection against the deleterious effects of cardiac ischemia/reperfusion, given to rats subjected to splanchnic artery occlusion and reperfusion (SAO/R)-induced splanchnic injury. 2. RLX (30 ng kg(-1), 15 min. before reperfusion) significantly reduced the drop of blood pressure and high mortality rate caused by SAO/R. RLX also reduced histopathological changes, leukocyte infiltration (myeloperoxidase) and expression of endothelial cell adhesion molecules in the ileum. RLX counteracted free radical-mediated tissue injury, as judged by significant decrease in the tissue levels of peroxidation and nitration products (malondialdehyde, nitrotyrosine), DNA damage markers (8-hydroxy-2'-deoxyguanosine, poly-ADP-ribosylated DNA) and consumption of tissue antioxidant enzymes (superoxide dismutase). As a result, RLX led to a reduction of ileal cell apoptosis (caspase 3, terminal deoxynucleotidyltransferase-mediated UTP end labeling). The effects of RLX appear specific, as inactivated RLX substituted for the bioactive hormone had no effects. 3. In conclusion, these results show that RLX exerts a clear-cut protective effect in SAO/R-induced splanchnic injury, likely due to endothelial protection, decreased leukocyte recruitment and hindrance of free radical-mediated tissue injury leading to cell death, lethal complications and high mortality rate. Thus, RLX could be used therapeutically in intestinal ischemia.

Animals↗
PubMed2006

Increased nitric oxide production in eating disorders.

Animal studies showed that nitric oxide (NO)/cyclic-GMP (cGMP) pathway is involved in the modulation of eating behavior. To address its role in eating disorders (ED), plasma nitrite and cGMP levels were studied in 50 ED patients (25 with Anorexia Nervosa, AN; 25 with Bulimia Nervosa, BN) and 20 sex- and age-matched controls (C). Nitrites (nmol/mg protein, mean+/-S.E.M.: any ED 1.01+/-0.29; AN 1.15+/-0.47; BN 0.88+/-0.36; C 0.25+/-0.07; p<0.01) and cGMP (nmol/ml plasma, mean+/-S.E.M.: any ED 2.58+/-0.60; AN 2.81+/-1.10; BN 2.41+/-0.70; C 0.11+/-0.05; p<0.01) were significantly higher in ED patients than in C. Nitrite and cGMP levels inversely correlated with BMI in AN patients (nitrites: r=-0.62 p<0.01; cGMP r=-0.45 p<0.05) but not in BN patients (nitrites: r=-0.15 p=0.49; cGMP: r=-0.05 p=0.13) or in control subjects (nitrites: r=0.11 p=0.98; cGMP r=0.37 p=0.32). Significant correlations were also present in bulimic patients between nitrite levels, frequency of binges and several psychopathological dimensions, as assessed through the EDE. This is the first evidence of an alteration of the NO pathway in ED patients. Further studies are needed to ascertain whether an increase in NO levels plays a possible role in the pathogenesis of ED.

Adult↗
PubMed2006

Gender role, eating disorder symptoms, and body image concern in ballet dancers.

OBJECTIVE: Our objective was to evaluate the relationships between gender role, eating behavior, and body image in nonprofessional female ballet dancers. METHODS: One hundred ten female ballet dancers and 59 controls were administered the Bem Sex Role Inventory, the Eating Disorder Examination (EDE), the Body Uneasiness Test (BUT), and the Beck Depression Inventory. RESULTS: Ballet dancers scored higher than controls in most of the items evaluating body image and eating behaviors; a high number of ballet dancers with undifferentiated gender role were also observed. In the dancers group, male-typified subjects showed higher median scores of EDE and BUT scales, while in the control group, the highest median scores of EDE and BUT scales were found in undifferentiated subjects. CONCLUSION: Ballet schools' cultural pressure towards an ideal of leanness could interfere with the process of gender role acquisition. Ballet dancers appear to be overconcerned with performance; this could reinforce the internalization of several constructs that are generally considered as typically male.

Adolescent↗
PubMed2006

Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells.

Cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LOX) are key enzymes involved in arachidonic acid metabolism. Their products, prostaglandins and leukotrienes, are involved in colorectal tumor development. We aimed at evaluating whether combined blocking of the COX-2 and 5-LOX pathways might have additive antitumor effects in colorectal cancer. The expression/activity of COX-2 and 5-LOX were assessed in 24 human colorectal cancer specimens. The effects of the COX-2 inhibitor celecoxib and the 5-LOX inhibitor MK886 on prostaglandin E(2) and cysteinyl leukotriene production, tumor cell proliferation, cell apoptosis, and Bcl-2/Bax expression were evaluated in the Caco-2 and HT29 colon cancer cells. We also investigated the effect of the enzymatic inhibition on mitochondrial membrane depolarization, one of the most important mechanisms involved in ceramide-induced apoptosis. Up-regulation of the COX-2 and 5-LOX pathways was found in the tumor tissue in comparison with normal colon mucosa. Inhibition of either COX-2 or 5-LOX alone resulted in activation of the other pathway in colon cancer cells. Combined treatment with 10 micromol/L celecoxib and MK886 could prevent this activation and had additive effects on inhibiting tumor cell proliferation, inducing cell apoptosis, decreasing Bcl-2 expression, increasing Bax expression, and determining mitochondrial depolarization in comparison with treatment with either inhibitor alone. The administration of the ceramide synthase inhibitor fumonisin B1 could prevent some of these antineoplastic effects. In conclusion, our study showed that inhibition of 5-LOX by MK886 could augment the antitumor activity of celecoxib in human colorectal cancer.

Aged↗
PubMed2005

Reduction of antigen-induced respiratory abnormalities and airway inflammation in sensitized guinea pigs by a superoxide dismutase mimetic.

Reactive oxygen species have been implicated in the pathogenesis of asthma and, in atopic asthmatics, endogenous superoxide dismutase (SOD) enzyme levels are known to decrease. This suggests that replacing a failed endogenous SOD enzyme system with a mimetic of the endogenous enzyme would be beneficial and protective. In this study we demonstrate that removal of superoxide by the SOD mimetic (SODm) M40403 reduces the respiratory and histopathological lung abnormalities due to ovalbumin (OA) aerosol in a model of allergic asthma-like reaction in sensitized guinea pigs. Both respiratory abnormalities and bronchoconstriction in response to OA challenge are nearly absent in naïve animals, while they sharply became severe in sensitized animals. In addition, OA aerosol induced a reduction of MnSOD activity which was paralleled with bronchiolar lumen reduction, pulmonary air space hyperinflation, mast cell degranulation, eosinophil infiltration, bronchial epithelial cell apoptosis, increase in myeloperoxidase activity, malonyldialdehyde production and 8-hydroxy-2'-deoxyguanosine formation in the lung tissue, as well as elevation of PGD2 in the bronchoalveolar lavage fluid. Treatment with M40403 restored the levels of MnSOD activity and significantly reduced all the above parameters. In summary, our findings support the potential therapeutic use of SOD mimetics in asthma and anaphylactic reactions and account for a critical role for superoxide in acute allergic asthma-like reaction in actively sensitized guinea pig.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction.

To obtain further information on time course and mechanisms of cell death after poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, we used HeLa cells exposed for 1 h to the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. This treatment activated PARP-1 and caused a rapid drop of cellular NAD(H) and ATP contents, culminating 8-12 h later in cell death. PARP-1 antagonists fully prevented nucleotide depletion and death. Interestingly, in the early 60 min after challenge with N-methyl-N'-nitro-N-nitrosoguanidine, mitochondrial membrane potential and superoxide production significantly increased, whereas cellular ADP contents decreased. Again, these events were prevented by PARP-1 inhibitors, suggesting that PARP-1 hyperactivity leads to mitochondrial state 4 respiration. Mitochondrial membrane potential collapsed at later time points (3 h), when mitochondria released apoptosis-inducing factor and cytochrome c. Using immunocytochemistry and targeted luciferase transfection, we found that, despite an exclusive localization of PARP-1 and poly(ADP-ribose) in the nucleus, ATP levels first decreased in mitochondria and then in the cytoplasm of cells undergoing PARP-1 activation. PARP-1 inhibitors rescued ATP (but not NAD(H) levels) in cells undergoing hyper-poly(ADP-ribosyl)ation. Glycolysis played a central role in the energy recovery, whereas mitochondria consumed ATP in the early recovery phase and produced ATP in the late phase after PARP-1 inhibition, further indicating that nuclear poly(ADP-ribosyl)ation rapidly modulates mitochondrial functioning. Together, our data provide evidence for rapid nucleus-mitochondria cross-talk during hyper-poly(ADP-ribosyl)ation-dependent cell death.

Adenosine Diphosphate↗
PubMed2004

Effect of a plant histaminase on asthmalike reaction induced by inhaled antigen in sensitized guinea pig.

This study evaluates the effects of a copper amine oxidase (histaminase) purified from the pea seedling as a free or immobilized enzyme on asthmalike reactions to inhaled antigen in actively sensitized guinea pig in vivo. Male albino guinea pigs, sensitized with ovalbumin, were challenged with the antigen given by aerosol; free histaminase or CNBr-Sepharose immobilized histaminase was given intraperitoneally (20 microg, 3 or 24 h before antigen challenge) or by aerosol (4 microg, 30 min before or during ovalbumin aerosol). The following parameters were examined: latency time for the onset of respiratory abnormalities, cough severity score, and occurrence and duration of dyspnea. We also evaluated lung histopathology, mast cell degranulation, and lung myeloperoxidase and malonydialdehyde levels. Histaminase significantly reduced the severity of cough and the occurrence of dyspnea and delayed the onset of respiratory abnormalities. Both enzymes prevented bronchial constriction, pulmonary air space inflation, leukocyte infiltration (evaluated as myeloperoxidase activity), and lipoperoxidation of cell membranes (evaluated as malonyldialdehyde production). No relevant differences in pharmacological potency were noted between free or immobilized enzyme. This study provides evidence that histaminase counteracts acute allergic asthmalike reaction in actively sensitized guinea pigs, raising the possibility of new therapeutic strategies for allergic asthma in humans.

Administration, Inhalation↗
PubMed2004

The endocannabinoid 2-arachidonylglycerol decreases the immunological activation of Guinea pig mast cells: involvement of nitric oxide and eicosanoids.

The antigen-induced release of histamine from sensitized guinea pig mast cells was dose-dependently reduced by endogenous (2-arachidonylglycerol; 2AG) and exogenous [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP55,940)] cannabinoids. The inhibitory action afforded by 2AG and CP55,940 was reversed by N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide (SR144528), a selective cannabinoid 2 (CB(2)) receptor antagonist, and left unchanged by the selective CB(1) antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). The inhibitory action of 2AG and CP55,940 was reduced by the unselective nitric-oxide synthase (NOS) inhibitor N-monomethyl-L-arginine methylester (l-NAME) and reinstated by L-arginine, the physiological substrate. The inhibitory action of 2AG and CP55,940 was also reduced by the unselective cyclooxygenase (COX) inhibitor indomethacin and the selective COX-2 blocker rofecoxib. Both 2AG and CP55,940 significantly increased the production of nitrite from mast cells, which was abrogated by L-NAME and N-(3-(aminomethyl)benzyl)acetamidine (1400W), a selective inducible NOS (iNOS) inhibitor. Nitrite production consistently paralleled a CP55,940-induced increase in the expression of iNOS protein in mast cells. Both 2AG and CP55,940 increased the generation of prostaglandin E(2) from mast cells, which was abrogated by indomethacin and rofecoxib and parallel to the CP55,940-induced expression of COX-2 protein. Mast cell challenge with antigen was accompanied by a net increase in intracellular calcium levels. Both cannabinoid receptor ligands decreased the intracellular calcium levels, which were reversed by SR144528 and l-NAME. In unstimulated mast cells, both ligands increased cGMP levels. The increase was abrogated by SR144528, l-NAME, indomethacin, and rofecoxib. Our results suggest that 2AG and CP55,940 decreased mast cell activation in a manner that is susceptible to a CB(2) receptor antagonist and to inhibition of nitric oxide and prostanoid pathways.

Animals↗
PubMed2003

Relaxin inhibits the activation of human neutrophils: involvement of the nitric oxide pathway.

In animal models of inflammation, the pregnancy hormone relaxin was shown to reduce the recruitment of leukocytes, especially neutrophils, in inflamed tissues. The current study was designed to clarify whether relaxin could inhibit activation of isolated human neutrophils and, if so, whether the nitric oxide (NO) biosynthetic pathway was involved, as occurs in other relaxin targets. Human neutrophils were preincubated with 1, 10, and 100 nmol/liter porcine relaxin for 1 h before activation with N-formyl-Met-Leu-Phe (10 micromol/liter) or phorbol-12-myristate-13-acetate (0.1 micromol/liter). In selected experiments, the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 100 micromol/liter) was added to the samples 30 min before relaxin. In other experiments, chemically inactivated relaxin (10 nmol/liter) was substituted for authentic relaxin. Untreated, nonactivated neutrophils were the controls. Relaxin reduced significantly and in a concentration-dependent fashion the expression of the surface activation marker CD11b, as well as the generation of superoxide anion, the rise of intracellular Ca(2+), the release of cytoplasmic granules, and the chemotactic migration. These effects of relaxin were blunted by N(G)-monomethyl-L-arginine and could not be reproduced by inactivated relaxin. Relaxin also increased neutrophil inducible NO synthase expression and NO generation. This study provides evidence that relaxin inhibits the activation of human neutrophils stimulated by different proinflammatory agents. This novel property of relaxin could be of relevance in toning down maternal neutrophil activation during pregnancy, thereby counteracting the occurrence of pregnancy-related disorders such as preeclampsia, which is regarded as an excess maternal inflammatory response to pregnancy.

Calcium↗
PubMed2003

Carbon monoxide modulates the response of human basophils to FcepsilonRI stimulation through the heme oxygenase pathway.

We report the effects of exogenous and endogenous carbon monoxide (CO) on the immunological activation of human basophils. Hemin (1-100 microM), a heme oxygenase substrate analogue, significantly increased the formation of bilirubin from partially purified human basophils, thus indicating that these cells express heme oxygenase. This effect was reversed by preincubating the cells for 30 min with Zn-protoporphyrin IX (100 microM), a heme oxygenase inhibitor. Hemin (100 microM) also decreased immunoglobulin G anti-Fcepsilon (anti-IgE)-induced activation of basophils, measured by the expression of a membrane granule-associated protein, identified as cluster differentiation protein 63 (CD63), and by histamine release. These effects were reversed by Zn-protoporphyrin IX (100 microM), by oxyhemoglobin (HbO(2)), a CO scavenger (100 microM), and by 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), an inhibitor of the soluble guanylyl cyclase (100 microM). Exposure of basophils to exogenous CO (10 microM for 30 min) also decreased their activation, while nitrogen (N(2)) was ineffective. HbO(2) and ODQ reversed the inhibition, reversing both membrane protein CD63 expression and histamine release to basal values. Both hemin and exogenous CO significantly raised cGMP levels in basophils and blunted the rise of calcium levels caused by immunological activation. This study suggests that CO increases cGMP formation, which in turn induces a fall in intracellular Ca(2+) concentration, thereby resulting in the inhibition of human basophil activation.

Antibodies, Anti-Idiotypic↗
PubMed2003

Inducible nitric oxide synthase expression in human colorectal cancer: correlation with tumor angiogenesis.

To investigate the potential involvement of the nitric oxide (NO) pathway in colorectal carcinogenesis, we correlated the expression and the activity of inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded tissue sections. iNOS activity and cyclic GMP levels were assessed by specific biochemical assays. iNOS protein expression was determined by Western blot analysis. iNOS and VEGF mRNA levels were evaluated using Northern blot analysis. Both iNOS and VEGF expressions correlated significantly with intratumor microvessel density (r(s) = 0.31, P = 0.02 and r(s) = 0.67, P < 0.0001, respectively). A significant correlation was also found between iNOS and VEGF expression (P = 0.001). iNOS activity and cyclic GMP production were significantly higher in the cancer specimens than in the normal mucosa (P < 0.0001 and P < 0.0001, respectively), as well as in metastatic tumors than in nonmetastatic ones (P = 0.002 and P = 0.04, respectively). Western and Northern blot analyses confirmed the up-regulation of the iNOS protein and gene in the tumor specimens as compared with normal mucosa. NO seems to play a role in colorectal cancer growth by promoting tumor angiogenesis.

Antigens, CD↗
PubMed2003

[Cardiac complications of anorexia nervosa].

The death rate of anorexia nervosa (AN) patients is up to 30 times greater than that of age-matched normal women. Bradycardia, hypotension and mitral valve prolapse are cardiac abnormalities that can be frequently found in AN patients. Risk of death is substantially linked to QT prolongation, which could be due to hypokalemia (binge/purging type AN) or to a starvation-derived anatomical remodelling of the heart (restricting type AN). The principal risk factors are duration of illness > 10 years, chronic hypokalemia, plasmatic albumin chronically < 3.6 g/dl and absolute QT > or = 600 ms.

Acid-Base Imbalance↗
PubMed2002

A plant histaminase modulates cardiac anaphylactic response in guinea pig.

The effect of a copper amine oxidase (histaminase) purified from the pea seedling as free or immobilized enzyme on the response to specific antigen was studied in isolated hearts from actively sensitized guinea pigs. In vitro challenge with the specific antigen of hearts from actively sensitized animals evokes a positive inotropic and chronotropic effect, a coronary constriction, followed by dilation and an increase in the amount of histamine and nitrites, the oxidation product of nitric oxide, in the perfusates. In the presence of both forms of histaminases, the positive inotropic and chronotropic responses as well as the coronary constriction and the release of histamine were fully blocked. The amount of nitrites, appearing in the perfusates when anaphylaxis is elicited in the presence of both forms of histaminases, is significantly increased, as well as nitric oxide synthase activity and cyclic GMP content in cardiac tissue, while cardiac calcium overload was significantly prevented. These observations demonstrate that the decrease in the anaphylactic release of histamine and the subsequent abatement of the cardiac response to antigen can be accounted for by the inactivation by histaminase of the released histamine and by a stimulation of endogenous nitric oxide production.

Amine Oxidase (Copper-Containing)↗