41 results on '"Ghisu N"'
Search Results
2. A1 and A2a receptors mediate inhibitory effects of adenosine on the motor activity of human colon
- Author
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FORNAI, M., ANTONIOLI, L., COLUCCI, R., GHISU, N., BUCCIANTI, P., MARIONI, A., CHIARUGI, M., TUCCORI, M., BLANDIZZI, C., and DEL TACCA, M.
- Published
- 2009
- Full Text
- View/download PDF
3. Somatostatin inhibits colon cancer cell growth through cyclooxygenase-2 downregulation
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Colucci, R, Blandizzi, C, Ghisu, N, Florio, T, and Del Tacca, M
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- 2008
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- View/download PDF
4. Cholecystokinin CCK2 receptors mediate the peptideʼs inhibitory actions on the contractile activity of human distal colon via the nitric oxide pathway
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Fornai, M, Colucci, R, Antonioli, L, Crema, F, Buccianti, P, Chiarugi, M, Baschiera, F, Ghisu, N, Tuccori, M, Blandizzi, C, and Del Tacca, M
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- 2007
- Full Text
- View/download PDF
5. Atorvastatin prevents endothelial dysfunction in mesenteric arteries from SHR. Role of COX-2-derived contracting prostanoids
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Virdis, Agostino, Colucci, R, Versari, D, Ghisu, N, Fornai, Matteo, Antonioli, Luca, Duranti, Emiliano, Daghini, E, Giannarelli, C, Blandizzi, Corrado, Taddei, Stefano, and DEL TACCA, Mario
- Subjects
Lipid lowering drugs ,Hypertension ,Atorvastatin, Lipid lowering drugs, Endothelium, Cyclooxygenase-2, Hypertension ,Atorvastatin ,Endothelium ,Cyclooxygenase-2 - Published
- 2009
6. Control of colonic neuromuscular functions by A3 purinergic receptors in normal colon and in experimental colitis
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Antonioli, L., Fornai, M., Colucci, ROCCHINA LUCIA, Ghisu, N., Tuccori, M., Giron, MARIA CECILIA, Bin, Anna, Zoppellaro, Chiara, Castagliuolo, Ignazio, Gaion, ROSA MARIA, DEL TACCA, M., and Blandizzi, C.
- Published
- 2009
7. Functional Neuroplasticity in Acute Diverticulitis: Differential Regulation of Colonic Excitatory Nerve Pathways By Cyclooxygenase Isoforms
- Author
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MATTEO FORNAI, luca antonioli, Giorgio, R., Colucci, R., Ghisu, N., NUNZIA BERNARDINI, Tuccori, Marco, Buccianti, P., Massimo Chiarugi, Marioni, A., Del Tacca, M., and CORRADO BLANDIZZI
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acute diverticulitis ,human intestinal motility ,acute diverticulitis, cyclooxygenase isoforms, human intestinal motility ,cyclooxygenase isoforms - Published
- 2008
8. Functional neuroplasticity in acute diverticulitis differential regulation of colonic excitiatory nerve pathways by cycloxygenase isoforms
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Fornai, M, Antonioli, L, De Giorgio, R, Colucci, ROCCHINA LUCIA, Ghisu, N, Bernardini, N, Tuccori, M, Buccianti, P, Chiarugi, M, Marioni, A, Del Tacca, M, and Blandizzi, Corrado
- Published
- 2008
9. Somatostatin inhibits colon cancer cell growth through cyclooxygenase-2 down-regulation
- Author
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Colucci, R, Blandizzi, Corrado, Ghisu, N, Florio, T, and DEL TACCA, M.
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Mitogen-Activated Protein Kinase 1 ,Cyclooxygenase 2 Inhibitors ,Colon ,Somatostatin, Colon cancer, Cyclooxygenase-2 ,Down-Regulation ,Research Papers ,Colon cancer ,Cyclooxygenase 2 ,Colonic Neoplasms ,Gastrins ,Humans ,Caco-2 Cells ,Protein Tyrosine Phosphatases ,Cyclooxygenase-2 ,Somatostatin ,HT29 Cells ,Oligopeptides ,Protein Kinase C ,Cell Proliferation - Abstract
Cyclooxygenase-2 (COX-2) is expressed in colonic neoplasms, where it supports cell proliferation via prostaglandin E(2) (PGE(2)) production. This study investigated the effects of somatostatin-14 on COX-2 expression, PGE(2) production and proliferation in colon cancer cells.Human colon adenocarcinoma cell lines Caco-2, HT-29 and HCT116 were used. The following techniques were employed: colourimetric assay for cell growth; 5-bromo-2'-deoxyuridine assay for DNA synthesis; enzyme immunoassay for PGE(2); COX-2 mRNA silencing; RT-PCR or Western blot for somatostatin receptor subtypes, cyclooxygenase isoforms, phosphorylated-ERK-1/ERK-2 and phosphorylated-Akt.HT-29 and Caco-2 cells expressed COX-2 and somatostatin receptors (sst(3/4/5) and sst(3/5), respectively). HCT116 cells did express somatostatin receptors (sst(2/3/5)), but not COX-2. Somatostatin-14 inhibited basal COX-2 expression, PGE(2) production, DNA synthesis and growth in Caco-2 cells and these effects were prevented by BN81658 (sst(3) receptor antagonist). Basal proliferation of HT-29, HCT116 and COX-2-silenced Caco-2 cells was not affected by somatostatin-14. Stimulation of HT-29 cells with gastrin-17 elicited increments of ERK-1/ERK-2 and Akt phosphorylation, COX-2 expression, PGE(2) production, DNA synthesis and cell growth, which were all counteracted by somatostatin-14. Somatostatin-14-induced inhibition of COX-2 expression, PGE(2) production and DNA synthesis were blocked by BIM23056 (sst(5) receptor antagonist).Somatostatin decreases COX-2 expression and function in colon cancer cells via activation of sst(3) or sst(5) receptors, and these effects contribute to the inhibitory action of somatostatin on cell proliferation. These findings can be relevant to the development of therapeutic strategies based on the modulation of the COX-2 pathway.
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- 2008
10. Clinical efficacy of esomeprazole in the prevention and healing of digestive toxicity associated with non-steroidal anti-inflammatory drugs in elderly patients
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Blandizzi, Corrado, Tuccori, M., Colucci, R., Gori, Giovanni, Fornai, Matteo, Antonioli, Luca, Ghisu, N., and DEL TACCA, Mario
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Nonsteroidal antiinflammatory drugs ,Proton pump inhibitors ,Esomeprazole ,Non-steroidal anti-inflammatory drugs ,Esomeprazole, Proton pump inhibitors, Nonsteroidal antiinflammatory drugs - Published
- 2008
11. NSAID activated gene (NAG-1) plays a role in the impairing effects of cyclooxygenase inhibitors on gastric ulcer repair
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Colucci, R., Ghisu, N., Antonioli, L., MATTEO FORNAI, NUNZIA BERNARDINI, Ippolito, C., Del Tacca, M., and CORRADO BLANDIZZI
- Published
- 2008
12. Cholecystokinin CCK2 receptors mediate inhibitory actions of cholecystokinin on the contractile activity of human distal colon via the nitric oxide pathway
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Fornai, M, Colucci, ROCCHINA LUCIA, Antonioli, L, Crema, F, Buccianti, P, Chiarugi, M, Baschiera, F, Ghisu, N, Tuccori, M, Blandizzi, C, and DEL TACCA, M.
- Subjects
Colon ,Nitric oxide ,Enteric nervous system ,Cholecystokinin ,Cholecystokinin, Nitric oxide, Enteric nervous system, Colon - Published
- 2007
13. Anti-inflammatory effect of a novel adenosine deaminase inhibitor in experimental colitis
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Antonioli, L, Fornai, M, Colucci, ROCCHINA LUCIA, Ghisu, N, Da Settimo, F, Natale, G, Duranti, E, Virdis, A, Breschi, M, Blandizzi, C, and Del Tacca, M.
- Published
- 2007
14. Differential role of A1 and A2a purinergic receptors in the control of colonic neurumuscular function in the presence of experimental colitis
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Antonioli, L, Fornai, M, Blandizzi, C, Colucci, ROCCHINA LUCIA, Ghisu, N, Breschi, M, and Del Tacca, M.
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purinergic receptors, experimental colitis ,experimental colitis ,purinergic receptors - Published
- 2006
15. Characterization of mechanisms accounting for COX-2-mediated proliferative actions of gastrin on human colon cancer cells
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Colucci, ROCCHINA LUCIA, Blandizzi, Corrado, Vassalle, C, Tanini, M, Ghisu, N, Breschi, MARIA CRISTINA, and Del Tacca, M.
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Gastrin, COX-2 ,COX-2 ,Gastrin - Published
- 2004
16. The antiproliferative effect of somatostatin in human colon cancer cells is mediated by downregulation of COX-2 expression
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Colucci, Rocchina Lucia, CORRADO BLANDIZZI, Tanini, M., Ghisu, N., MARIA CRISTINA BRESCHI, and Del Tacca, M.
- Published
- 2003
17. Control of enteric neuromuscular functions by purinergic A(3) receptors in normal rat distal colon and experimental bowel inflammation.
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Antonioli, L, Fornai, M, Colucci, R, Ghisu, N, Tuccori, M, Awwad, O, Bin, A, Zoppellaro, C, Castagliuolo, I, Gaion, RM, Giron, MC, Blandizzi, C, Gaion, R M, and Giron, M C
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NEUROMUSCULAR system ,PURINERGIC receptors ,LABORATORY rats ,COLON (Anatomy) ,INFLAMMATION ,BIOLOGY experiments ,ADENOSINES - Abstract
Background and Purpose: Adenosine A(3) receptors mediate beneficial effects in experimental colitis, but their involvement in enteric neuromuscular functions during bowel inflammation is undetermined. This study investigated the regulatory role of A(3) receptors on colonic motility in the presence of experimental colitis.Experimental Approach: Colitis was induced in rats by 2,4-dinitrobenzenesulfonic acid. A(3) receptors and adenosine deaminase (ADA, adenosine catabolic enzyme) mRNA were examined by RT-PCR. Tissue distribution of A(3) receptors was detected by confocal immunofluorescence. The effects of 2,3-ethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate (MRS1523) (MRS, A(3) receptor antagonist), 2-chloro-N(6) -(3-iodobenzyl)-adenosine-5'-N-methyluronamide (2Cl-IB-MECA) (CIB, A(3) receptor agonist), dipyridamole (DIP, adenosine transport inhibitor) and ADA were assayed on contractile responses evoked by electrical stimulation (ES) or carbachol in colonic longitudinal muscle preparations (LMP).Key Results: RT-PCR showed A(3) receptors and ADA mRNA in normal colon and their increased level in inflamed tissues. Immunofluorescence showed a predominant distribution of A(3) receptors in normal myenteric ganglia and an increased density during colitis. MRS enhanced ES-induced cholinergic contractions in normal LMP, but was less effective in inflamed tissues. After pretreatment with dipyridamole plus ADA, to reduce extracellular adenosine, CIB decreased cholinergic motor responses of normal LMP to ES, with enhanced efficacy in inflamed LMP. A(3) receptor ligands did not affect carbachol-induced contractions in LMP from normal or inflamed colon.Conclusions and Implications: Normally, adenosine modulated colonic cholinergic motility via activation of A(3) receptors in the myenteric plexus. A(3) receptor-mediated tonic inhibitory control by adenosine was impaired in inflamed bowel, despite increased density of functioning and pharmacologically recruitable A(3) receptors. [ABSTRACT FROM AUTHOR]- Published
- 2010
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18. A1 and A2a receptors mediate inhibitory effects of adenosine on the motor activity of human colon.
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FORNAI, M., ANTONIOLI, L., COLUCCI, R., GHISU, N., BUCCIANTI, P., MARIONI, A., CHIARUGI, M., TUCCORI, M., BLANDIZZI, C., and DEL TACCA, M.
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ADENOSINES ,ANIMAL models in research ,REVERSE transcriptase polymerase chain reaction ,GUANETHIDINE ,LIGANDS (Biochemistry) - Abstract
Experimental evidence in animal models suggests that adenosine is involved in the regulation of digestive functions. This study examines the influence of adenosine on the contractile activity of human colon. Reverse transcription-polymerase chain reaction revealed A
1 and A2a receptor expression in colonic neuromuscular layers. Circular muscle preparations were connected to isotonic transducers to determine the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; A1 receptor antagonist), ZM 241385 (A2a receptor antagonist), CCPA (A1 receptor agonist) and 2-[(p-2-carboxyethyl)-phenethylamino]-5′- N-ethyl-carboxamide-adenosine (CGS 21680; A2a receptor agonist) on motor responses evoked by electrical stimulation or carbachol. Electrically evoked contractions were enhanced by DPCPX and ZM 241385, and reduced by CCPA and CGS 21680. Similar effects were observed when colonic preparations were incubated with guanethidine (noradrenergic blocker), L-732,138, GR-159897 and SB-218795 (NK receptor antagonists). However, in the presence of guanethidine, NK receptor antagonists and Nω -propyl-l-arginine (NPA; neuronal nitric oxide synthase inhibitor), the effects of DPCPX and CCPA were still evident, while those of ZM 241385 and CGS 21680 no longer occurred. Carbachol-induced contractions were unaffected by A2a receptor ligands, but they were enhanced or reduced by DPCPX and CCPA, respectively. When colonic preparations were incubated with guanethidine, NK antagonists and atropine, electrically induced relaxations were partly reduced by ZM 241385 or NPA, but unaffected by DPCPX. Dipyridamole or application of exogenous adenosine reduced electrically and carbachol-evoked contractions, whereas adenosine deaminase enhanced such motor responses. In conclusion, adenosine exerts an inhibitory control on human colonic motility. A1 receptors mediate direct modulating actions on smooth muscle, whereas A2a receptors operate through inhibitory nitrergic nerve pathways. [ABSTRACT FROM AUTHOR]- Published
- 2009
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19. Cholecystokinin CCK2 receptors mediate the peptide's inhibitory actions on the contractile activity of human distal colon via the nitric oxide pathway.
- Author
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Fornai, M., Colucci, R., Antonioli, L., Crema, F., Buccianti, P., Chiarugi, M., Baschiera, F., Ghisu, N., Tuccori, M., Blandizzi, C., and Del Tacca, M.
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CHOLECYSTOKININ ,COLON (Anatomy) ,INTESTINAL abnormalities ,NITRIC oxide ,PHARMACOLOGY - Abstract
Background and purpose:Cholecystokinin is known to exert stimulant actions on intestinal motility via activation of type 1 cholecystokinin receptors (CCK
1 ). However, the role played by cholecystokinin 2 (CCK2 ) receptors in the regulation of gut motility remains undetermined. This study was designed to examine the influence of CCK2 receptors on the contractile activity of human distal colon.Experimental approach:The effects of compounds acting on CCK2 receptors were assessed in vitro on motor activity of longitudinal smooth muscle, under basal conditions as well as in the presence of KCl-induced contractions or transmural electrical stimulation.Key results:Cholecystokinin octapeptide sulphate induced concentration-dependent contractions which were enhanced by GV150013 (CCK2 receptor antagonist; +57% at 0.01 μM). These effects were unaffected by tetrodotoxin. The enhancing actions of GV150013 on contractions evoked by cholecystokinin octapeptide sulphate were unaffected by Nω -propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by Nω -nitro-L-arginine methylester (L-NAME, non-selective nitric oxide synthase inhibitor). In the presence of KCl-induced contractions, cholecystokinin octapeptide sulphate elicited concentration-dependent relaxations (-36%), which were unaffected by NPA, but were counteracted by GV150013 or L-NAME. The application of electrical stimuli evoked phasic contractions which were enhanced by GV150013 (+41 % at 0.01 μM).Conclusions and implications:CCK2 receptors mediate inhibitory actions of cholecystokinin on motor activity of human distal colon. It is suggested that CCK2 receptors exert their modulating actions through a nitric oxide pathway, independent of the activity of the neuronal nitric oxide synthase isoform.British Journal of Pharmacology (2007) 151, 1246–1253; doi:10.1038/sj.bjp.0707339; published online 18 June 2007 [ABSTRACT FROM AUTHOR]- Published
- 2007
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20. OC.10.5 ASSOCIATION OF THE SEROTONIN TRANSPORTER 5HTTLPR POLYMORPHISM WITH INCREASED SYMPTOM SEVERITY IN PATIENTS WITH IRRITABLE BOWEL SYNDROME
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Gambaccini, D., Bellini, M., Colucci, R., Ghisu, N., Rossi, G., Costa, F., Mismas, V., Tonini, M., Del Tacca, M., Blandizzi, C., and Marchi, S.
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- 2010
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21. OC3.07.6 SEROTONIN TRANSPORTER (5HTTLPR) POLYMORPHISM, CLINICAL VARIANTS AND SYMPTOM SEVERITY IN PATIENTS WITH IRRITABLE BOWEL SYNDROME
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Gambaccini, D., Bellini, M., Colucci, R., Ghisu, N., Blandizzi, C., Costa, F., Mumolo, M.G., Ricchiuti, A., Rossi, G., Tonini, M., Del Tacca, M., and Marchi, S.
- Published
- 2008
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22. Effects of a bicarbonate-alkaline mineral water on digestive motility in experimental models of functional intestinal alterations
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Fornat, M., Antonioli, L., Colucci, R., Ghisu, N., Blandizzi, C., and Del Tacca, M.
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- 2006
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23. A2a purinergic receptors are involved in the control of colonic motility in an experimental model of inflammatory bowel disease
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Antonioli, L., Fornai, M., Colucci, R., Ghisu, N., Blandizzi, C., and Tacca, M. Del
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- 2006
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24. Safety concerns associated with the use of serotonin reuptake inhibitors and other serotonergic/noradrenergic antidepressants during pregnancy: a review.
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Tuccori M, Testi A, Antonioli L, Fornai M, Montagnani S, Ghisu N, Colucci R, Corona T, Blandizzi C, and Del Tacca M
- Abstract
BACKGROUND: There is ongoing debate about the safety of selective serotonin reuptake inhibitors (SSRIs) and other serotonergic/noradrenergic antidepressants when used during pregnancy. OBJECTIVE: This article reviews the available literature on the main safety concerns associated with the use of SSRIs and other serotonergic/noradrenergic antidepressants (serotonin-norepinephrine reuptake inhibitors, norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants) during pregnancy. METHODS: English-language reports of analytical and descriptive studies, including case reports, case series, and meta-analyses, were identified through searches of MEDLINE, EMBASE, and PsycINFO (1966-April 2009). The search terms were fluoxetine, paroxetine, sertraline, Citalopram, escitalopram, fluvoxamine, venlafaxine, mirtazapine, reboxetine, duloxetine, SSRI, SNRI, NaSSA, and NRI in association with depression, pregnancy, prenatal exposure, miscarriage, spontaneous abortion, malformation, in utero exposure, and neonatal complications. RESULTS: Paroxetine has been associated with significant risks of major malformation, particularly cardiac defects, when used during pregnancy. Significant associations between maternal exposure to SSRIs and both persistent pulmonary hypertension of the newborn and a self-limiting neonatal behavioral syndrome have been reported in a number of recent original studies and meta-analyses. Some studies have suggested a relationship between the use of SSRIs or other serotonergic/noradrenergic antidepressants and the occurrence of miscarriage, although these studies had methodologic limitations that affected the strength of the data. Evidence for a possible association between in utero exposure to SSRIs or other serotonergic/noradrenergic antidepressants and alterations in neurobehavioral development, bleeding, and QTc-interval prolongation is currently weak. CONCLUSION: The available evidence suggests that SSRIs and other serotonergic/noradrenergic antidepressants should be used with caution during pregnancy, with careful follow-up of infants exposed to these agents in utero. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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25. Influence of the serotonin transporter 5HTTLPR polymorphism on symptom severity in irritable bowel syndrome.
- Author
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Colucci R, Gambaccini D, Ghisu N, Rossi G, Costa F, Tuccori M, De Bortoli N, Fornai M, Antonioli L, Ricchiuti A, Mumolo MG, Marchi S, Blandizzi C, and Bellini M
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- Adult, Female, Genotype, Humans, Male, Irritable Bowel Syndrome genetics, Polymorphism, Genetic genetics, Serotonin Plasma Membrane Transport Proteins genetics
- Abstract
5HTTLPR polymorphism of serotonin transporter yields short (S) and long (L) alleles. SS and LS genotypes are associated with reduced expression of serotonin transporter. This cross-sectional study investigated the association of 5HTTLPR with symptom severity of irritable bowel syndrome (IBS). Patients with IBS (Rome III) and healthy controls were included. Genomic DNA was extracted from saliva, and 5HTTLPR alleles were assessed by polymerase chain reaction. IBS symptom severity was evaluated by means of IBS-SSS questionnaire. Two hundreds and four IBS patients (159 females; mean age: 39.6±12.3 years; 106 with constipation: C-IBS; 98 with diarrhea: D-IBS) and 200 healthy controls (154 females; mean age: 40.4±15.8 years) were enrolled. The overall IBS-SSS value was higher in LS/SS than LL patients (319.0±71.5 versus 283.8±62.3; P = 0.0006). LS/SS patients had also higher values of abdominal pain (59.7±21.0 versus 51.0±18.8; P = 0.020) and bowel dissatisfaction (80.1±23.9 versus 70.5±22.8; P = 0.035). The overall IBS-SSS values in C-IBS and D-IBS patients were 317.2±68.3 and 296.1±71.4, respectively (P = 0.192), with significantly higher values for abdominal distension (65.0±24.4 versus 51.4±24.8; P = 0.0006), but not for bowel dissatisfaction (80.5±21.7 versus 72.9±25.7; P = 0.138). Frequencies of 5HTTLPR genotypes did not differ significantly when comparing IBS patients (overall or upon stratification in C-IBS and D-IBS) with healthy controls. In conclusion, the LS and SS genotypes are significantly correlated with IBS symptom severity, although their possible direct causal role remains to be proven. In addition, the present findings do not support an association of 5HTTLPR with IBS or its clinical presentation in terms of bowel habit predominance.
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- 2013
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26. Differential recruitment of high affinity A1 and A2A adenosine receptors in the control of colonic neuromuscular function in experimental colitis.
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Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, Tuccori M, Del Tacca M, and Blandizzi C
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- 5'-Nucleotidase metabolism, Adenosine analogs & derivatives, Adenosine pharmacology, Adenosine A1 Receptor Agonists pharmacology, Adenosine A1 Receptor Antagonists pharmacology, Adenosine A2 Receptor Agonists pharmacology, Adenosine A2 Receptor Antagonists pharmacology, Animals, Benzenesulfonates, Colitis metabolism, Colitis physiopathology, Colon metabolism, Colon physiopathology, Disease Models, Animal, In Vitro Techniques, Male, Muscle Contraction drug effects, Muscle, Smooth drug effects, Muscle, Smooth innervation, Muscle, Smooth physiopathology, Rats, Rats, Sprague-Dawley, Xanthines pharmacology, Colitis drug therapy, Colon drug effects, Receptor, Adenosine A1 metabolism, Receptors, Adenosine A2 metabolism
- Abstract
This study investigated the expression of A(1) and A(2A) receptors in the rat colonic neuromuscular compartment, and characterized their roles in the control of motility during inflammation. Colitis was induced by 2,4-dinitrobenzenesulfonic acid. A(1), A(2A) receptors, and ecto-5'-nucleotidase (CD73, adenosine producing enzyme) mRNA expression was examined by RT-PCR. The effects of DPCPX (A(1) receptor antagonist), CCPA (A(1) receptor agonist), 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (A(2A) receptor antagonist), 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (A(2A) receptor agonist), AOPCP (CD73 inhibitor) were tested on electrically or carbachol-evoked contractions in colonic longitudinal muscle preparations. In normal colon, RT-PCR revealed the presence of A(1) receptors, A(2A) receptors and CD73, and an increased expression of A(2A) receptors and CD73 was detected in inflamed tissues. In normal colon, DPCPX or 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol enhanced electrically-induced contractions, while in inflamed preparations the effect of DPCPX no longer occurred. In normal colon, CCPA or 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl] benzenepropanoic acid hydrochloride decreased electrically-induced contractions. Under inflammation, 4-[2-[[6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl] benzenepropanoic acid hydrochloride reduced electrically evoked contractions with higher efficacy, while the inhibition by CCPA remained unchanged. A(1) and A(2A) receptor ligands did not affect carbachol-induced contractions. AOPCP enhanced electrically-induced contractions and prevented the contractile effects of 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol, without interfering with DPCPX, both in normal and inflamed colons. These results indicate that, in normal colon, both A(1) and A(2A) receptors contribute to the inhibitory control of motor functions at neuronal level. Under bowel inflammation, A(1) receptor loses its modulating actions, while the recruitment of A(2A) receptor by CD73-dependent endogenous adenosine drives an enhanced inhibitory control of colonic neuromotility., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2011
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27. The blockade of adenosine deaminase ameliorates chronic experimental colitis through the recruitment of adenosine A2A and A3 receptors.
- Author
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Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, Tuccori M, Da Settimo F, La Motta C, Natale G, Duranti E, Virdis A, and Blandizzi C
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- Adenine pharmacology, Adenine therapeutic use, Adenosine Deaminase biosynthesis, Animals, Blotting, Western, Body Weight drug effects, Chronic Disease, Colitis enzymology, Colitis immunology, Colitis metabolism, Colon drug effects, Colon enzymology, Colon immunology, Colon metabolism, Cytokines immunology, Disease Models, Animal, Enzyme Inhibitors pharmacology, Male, Organ Size drug effects, Pyrazoles pharmacology, Pyrimidines pharmacology, Rats, Rats, Sprague-Dawley, Adenine analogs & derivatives, Adenosine Deaminase Inhibitors, Colitis prevention & control, Enzyme Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Receptor, Adenosine A2A metabolism, Receptor, Adenosine A3 metabolism
- Abstract
Adenosine modulates immune/inflammatory reactions. This study investigates the expression of adenosine deaminase in the inflamed colon, the effects of adenosine deaminase inhibitors on established colitis, and the recruitment of adenosine receptors by endogenous adenosine after adenosine deaminase blockade. Adenosine deaminase expression was determined by Western blot. The effects of 4-amino-2-(2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine (APP; a novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; a reference adenosine deaminase inhibitor), dexamethasone, and selective adenosine receptor antagonists were tested in rats with 2,4-dinitrobenzenesulfonic acid-induced colitis. Systemic (food intake, body and spleen weight) and colonic [macroscopic/microscopic damage, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA)] inflammatory parameters were assessed. Test drugs were administered intraperitoneally for 6 days, starting at day 5 from colitis induction. Adenosine deaminase was detected in normal colon, and its expression was increased in inflamed tissues. Colitis was associated with decreased food intake and body weight, augmented spleen weight, and increased levels of colonic TNF-α, IL-6, and MDA. APP or EHNA, but not dexamethasone, improved food intake and body weight. APP, EHNA, and dexamethasone counteracted the increments of spleen weight, ameliorated macroscopic and microscopic indexes of inflammation, and reduced TNF-α, IL-6, and MDA levels. The beneficial effects of APP and EHNA on inflammatory parameters were prevented by the pharmacological blockade of A(2A) or A(3) receptors, but not A(1) or A(2B). The present results show that: 1) bowel inflammation is associated with an enhanced adenosine deaminase expression; and 2) the anti-inflammatory actions of adenosine deaminase inhibitors against chronic established colitis depend on the sparing of endogenous adenosine, leading to enhanced A(2A) and A(3) receptor activation.
- Published
- 2010
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28. Emerging role of cyclooxygenase isoforms in the control of gastrointestinal neuromuscular functions.
- Author
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Fornai M, Antonioli L, Colucci R, Bernardini N, Ghisu N, Tuccori M, De Giorgio R, Del Tacca M, and Blandizzi C
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- Animals, Cyclooxygenase Inhibitors therapeutic use, Enteric Nervous System physiopathology, Gastrointestinal Diseases drug therapy, Gastrointestinal Diseases physiopathology, Gastrointestinal Tract drug effects, Gastrointestinal Tract innervation, Humans, Isoenzymes, Mucous Membrane enzymology, Mucous Membrane innervation, Muscle, Smooth drug effects, Muscle, Smooth innervation, Gastrointestinal Diseases enzymology, Gastrointestinal Motility drug effects, Gastrointestinal Tract enzymology, Muscle, Smooth enzymology, Prostaglandin-Endoperoxide Synthases metabolism
- Abstract
Since the discovery of two cyclooxygenase isoforms (COX-1, COX-2), efforts have been made to characterize the roles played by these enzymes in the regulation of physiological functions, as well as to explore their involvement in the pathophysiology of inflammatory disorders. In the digestive tract, the majority of evidence has been obtained at mucosal level, where both isoforms regulate various functions, and contribute to the development of inflammatory and neoplastic disorders. The role of COX isoforms in the gut neuromuscular compartment, where their expression has been detected in different species, is still unclear. However, the characterization of actions exerted by COX-derived prostanoids on gut motility has been under investigation for many years, and it is becoming increasingly appreciated that these mediators subserve complex regulatory patterns of COX on digestive motility. More recently, several studies have strengthened the concept that both COX-1 and COX-2 are involved in the modulation of gastrointestinal neuromuscular activity under normal conditions, and that changes in their regulatory activities occur in the presence of various digestive disorders, including inflammatory bowel diseases and postoperative ileus. Despite a large body of preclinical evidence, studies aimed at translating these findings into clinically relevant applications are needed, in an attempt to identify novel therapeutic approaches for treatment of gut disorders associated with motility alterations. This review illustrates and discusses current knowledge of the roles played by COX pathways in the regulation of gastrointestinal neuromuscular functions, both under normal conditions and in the presence of gut disorders.
- Published
- 2010
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29. Atorvastatin prevents endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats: role of cyclooxygenase 2-derived contracting prostanoids.
- Author
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Virdis A, Colucci R, Versari D, Ghisu N, Fornai M, Antonioli L, Duranti E, Daghini E, Giannarelli C, Blandizzi C, Taddei S, and Del Tacca M
- Subjects
- Analysis of Variance, Animals, Atorvastatin, Blotting, Western, Cyclooxygenase 1 metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Administration Schedule, Endothelium, Vascular physiopathology, Male, Malondialdehyde metabolism, Mesenteric Arteries physiopathology, Probability, Prostaglandins metabolism, RNA metabolism, Random Allocation, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Reverse Transcriptase Polymerase Chain Reaction, Sensitivity and Specificity, Vasodilation physiology, Cyclooxygenase 2 metabolism, Endothelium, Vascular drug effects, Heptanoic Acids pharmacology, Mesenteric Arteries drug effects, Pyrroles pharmacology, Vasodilation drug effects
- Abstract
We investigated the effect of atorvastatin on cyclooxygenase (COX) contribution to endothelial dysfunction in spontaneously hypertensive rat (SHR) mesenteric resistance arteries. Atorvastatin (10 mg/kg per day, oral gavage) or its vehicle was administered for 2 weeks to male SHR or Wistar-Kyoto rats. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In Wistar-Kyoto rats, relaxation to acetylcholine was inhibited by N(G)-nitro-L-arginine methyl ester and unaffected by SC-560 (COX-1 inhibitor), DuP-697 (COX-2 inhibitor), or ascorbic acid. In SHRs, the response to acetylcholine was attenuated, less sensitive to N(G)-nitro-L-arginine methyl ester, unaffected by SC-560, and enhanced by DuP-697 or SQ-29548 (thromboxane-prostanoid receptor antagonist) to a similar extent. Endothelium-dependent relaxation was normalized by ascorbic acid or apocynin (NADPH oxidase inhibitor), which also restored the inhibition by N(G)-nitro-L-arginine methyl ester. In atorvastatin-treated SHRs, relaxation to acetylcholine was normalized, fully sensitive to N(G)-nitro-L-arginine methyl ester, and not affected by SC-560, DuP-697, SQ 29548, or antioxidants. Dihydroethidium assay showed an increased intravascular superoxide generation in SHRs, which was abrogated by atorvastatin. RT-PCR revealed a COX-2 induction in SHR arteries, which was downregulated by atorvastatin. The release of prostacyclin and 8-isoprostane was higher from SHR than Wistar-Kyoto mesenteric vessels. COX-2 inhibition and apocynin decreased 8-isoprostane without affecting prostacyclin levels. Atorvastatin increased phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS(1177), and inducible NO synthase levels in SHR mesenteric vessels and decreased 8-isoprostane release. In conclusion, COX-2-derived 8-isoprostane contributes to endothelial dysfunction in SHR mesenteric arteries. Atorvastatin restores NO availability by increasing phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS(1177), and inducible NO synthase levels and by abrogating vascular NADPH oxidase-driven superoxide production, which also results in a downregulation of COX-2-dependent 8-isoprostane generation.
- Published
- 2009
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30. Effects of pantoprazole on ulcer healing delay associated with NSAID treatment.
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Fornai M, Colucci R, Antonioli L, Ghisu N, Tuccori M, Blandizzi C, and Del Tacca M
- Subjects
- 2-Pyridinylmethylsulfinylbenzimidazoles administration & dosage, 2-Pyridinylmethylsulfinylbenzimidazoles pharmacology, Acetic Acid, Animals, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Ulcer Agents administration & dosage, Anti-Ulcer Agents pharmacology, Anti-Ulcer Agents therapeutic use, Blotting, Western, Caspase 3 metabolism, Disease Models, Animal, Famotidine administration & dosage, Famotidine pharmacology, Famotidine therapeutic use, Gastric Acid metabolism, Male, Oxidative Stress drug effects, Pantoprazole, Proliferating Cell Nuclear Antigen metabolism, Proton Pump Inhibitors administration & dosage, Proton Pump Inhibitors pharmacology, Rats, Stomach Ulcer metabolism, 2-Pyridinylmethylsulfinylbenzimidazoles therapeutic use, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Proton Pump Inhibitors therapeutic use, Stomach Ulcer prevention & control, Wound Healing drug effects
- Abstract
Nonsteroidal anti-inflammatory drugs delay gastric ulcer healing, and the ability of proton pump inhibitors to counteract this detrimental effect is debated. This study evaluates the effects of pantoprazole on experimental gastric ulcer healing in the presence of indomethacin. Rats with acetic-acid-induced gastric ulcers were orally treated for 3 or 7 days with pantoprazole (15 micromol/kg/day) or famotidine (20 micromol/kg/day), alone or in combination with indomethacin (3 micromol/kg/day). Ulcerated tissues were processed to assess ulcer area, malondialdehyde, proliferating cell nuclear antigen (PCNA) and cleaved caspase-3. Experiments on pylorus-ligated rats indicated that pantoprazole and famotidine were employed at equivalent inhibitory doses on gastric acid secretion (-67.9% and -64.5%, respectively). Indomethacin delayed ulcer healing both at days 3 and 7 (+22 and +35 mm(2) vs control ulcer, respectively). At day 3, pantoprazole was more effective than famotidine in promoting ulcer healing in indomethacin-treated animals (-53.6 and -31.6 mm(2) vs indomethacin, respectively). Malondialdehyde levels and caspase-3 activation in ulcers were increased by indomethacin (+79% and +3.7 folds vs control ulcer, respectively), and these effects were counteracted by pantoprazole (-77.9% and -3.5 folds vs indomethacin, respectively), but not famotidine. Increments of ulcer PCNA expression (+2.5 folds vs normal) were enhanced further by pantoprazole or famotidine, alone or in combination with indomethacin (+8.6 and +10.3 folds vs normal, respectively). Similar results were obtained after 7-day treatments of ulcerated animals with test drugs. It is concluded that, along with acid suppression, pantoprazole exerts acid-independent effects on ulcer healing, which can be ascribed to a decrease in tissue oxidation and apoptosis.
- Published
- 2009
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31. Genetic polymorphisms of thiopurine S-methyltransferase in a cohort of patients with systemic autoimmune diseases.
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Tani C, Mosca M, Colucci R, Gori G, d'Ascanio A, Ghisu N, Fornai M, Di Paolo A, Blandizzi C, Del Tacca M, and Bombardieri S
- Subjects
- Adult, Aged, Antimetabolites metabolism, Azathioprine metabolism, Cohort Studies, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged, White People, Young Adult, Antimetabolites adverse effects, Autoimmune Diseases drug therapy, Autoimmune Diseases genetics, Azathioprine adverse effects, Methyltransferases genetics, Polymorphism, Single Nucleotide
- Abstract
Objectives: Azathioprine (AZA) is a purine antimetabolite, prodrug widely used as a disease modifying drug in several rheumatic conditions. The aim of the present study was to evaluate the prevalence of TPMT genetic polymorphisms in a cohort of Italian Caucasian patients affected by rheumatic diseases and treated with AZA, and to establish correlations with the tolerability of AZA treatment., Results: Seventy-eight Caucasian patients, 16 males and 62 females, median age 41 years (min-max: 24-76) were enrolled. At the time of evaluation, the median duration of treatment with AZA was 8 months (min-max: 2-150 months); the median dose of AZA per kg of body weight was 1.42 mg (min-max: 0.5-2). Among the 78 patients evaluated, 76 presented a wild type genotype (TPMT *1), while polymorphic alleles were identified in 2 patients (2.6%). Twenty-five patients (32%) experienced different types of adverse events (AE) under AZA treatment. Eighteen patients (23.1%) discontinued AZA because of AE. No correlation was observed between polymorphic TPMT alleles and the development of AE., Conclusions: Our analysis supports the view that TPMT genotyping alone is not sufficient to adequately personalize the AZA dosage in rheumatic patients. Further studies based on phenotypic analysis of TPMT enzyme and assay of AZA metabolite appear to be required.
- Published
- 2009
32. Role of coxibs in the strategies for gastrointestinal protection in patients requiring chronic non-steroidal anti-inflammatory therapy.
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Blandizzi C, Tuccori M, Colucci R, Fornai M, Antonioli L, Ghisu N, and Del Tacca M
- Subjects
- Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Aspirin adverse effects, Cyclooxygenase Inhibitors administration & dosage, Humans, Stomach Ulcer chemically induced, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Cyclooxygenase Inhibitors pharmacology, Gastric Mucosa drug effects, Intestinal Mucosa drug effects
- Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs due to their high efficacy in the treatment of pain, fever, inflammation and rheumatic disorders. However, their use is associated with the occurrence of adverse effects at the level of digestive tract, ranging from dyspeptic symptoms, gastrointestinal erosions and peptic ulcers to more serious complications, such as overt bleeding or perforation. To overcome problems related to NSAID-induced digestive toxicity, different therapeutic strategies can presently be considered, including the co-administration of drugs endowed with protective activity on the upper gastrointestinal tract, such as the proton pump inhibitors, or the prescription of coxibs, which have been clinically developed as anti-inflammatory/analgesic drugs characterized by reduced damaging activity on gastrointestinal mucosa. The availability of different treatment options, to reduce the risk of NSAID-induced adverse digestive effects, has fostered intensive preclinical and clinical research aimed at addressing a number of unresolved issues and to establish rational criteria for an appropriate use of coxibs in the medical practice. Particular attention is being paid to the management of patients with high degrees of digestive risk, resulting by concomitant treatment with low-dose aspirin for anti-thrombotic prophylaxis or ongoing symptomatic gastroduodenal ulcers. The present review discusses the most relevant lines of evidence concerning the position of coxibs in the therapeutic strategies for gastrointestinal protection in patients who require NSAID therapy and hold different levels of risk of developing adverse effects at the level of digestive tract.
- Published
- 2009
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33. Inducible nitric oxide synthase is involved in endothelial dysfunction of mesenteric small arteries from hypothyroid rats.
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Virdis A, Colucci R, Fornai M, Polini A, Daghini E, Duranti E, Ghisu N, Versari D, Dardano A, Blandizzi C, Taddei S, Del Tacca M, and Monzani F
- Subjects
- Allopurinol pharmacology, Animals, Ascorbic Acid pharmacology, Endothelium, Vascular metabolism, Enzyme Inhibitors pharmacology, Hypothyroidism chemically induced, Hypothyroidism metabolism, Hypothyroidism pathology, Male, Mesenteric Arteries metabolism, Methimazole, NADPH Oxidases antagonists & inhibitors, NADPH Oxidases physiology, NG-Nitroarginine Methyl Ester pharmacology, Nitric Oxide metabolism, Nitric Oxide Synthase Type II metabolism, Rats, Rats, Wistar, Superoxides metabolism, Thyroxine pharmacology, Vasodilation drug effects, Endothelium, Vascular physiopathology, Hypothyroidism physiopathology, Mesenteric Arteries physiopathology, Nitric Oxide Synthase Type II physiology
- Abstract
The time-dependent effects of mild hypothyroidism on endothelial function were assessed in rat mesenteric arteries. Male Wistar rats were treated with methimazole (MMI; 0.003%) or placebo up to 16 wk. Endothelial function of mesenteric small arteries was assessed by pressurized myograph. MMI-treated animals displayed a decrease in serum thyroid hormones, an increment of plasma TSH and inflammatory cytokines, and a blunted vascular relaxation to acetylcholine, as compared with controls. Endothelial dysfunction resulted from a reduced nitric oxide (NO) availability caused by oxidative excess. Vascular-inducible NO synthase (iNOS) expression was up-regulated. S-methylisothiourea (an iNOS inhibitor) normalized endothelium-dependent relaxations and restored NO availability in arteries from 8-wk MMI-animals and partly ameliorated these alterations in 16-wk MMI rats. Similar results were obtained when MMI-induced hypothyroidism was prevented by T(4) replacement. Among controls, an impaired NO availability, secondary to oxidative excess, occurred at 16 wk, and it was less pronounced than in age-matched MMI animals. Both endothelial dysfunction and oxidant excess secondary to aging were prevented by apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor). Mesenteric superoxide production was reduced by S-methylisothiourea and T(4) replacement in MMI animals and abolished by apocynin in controls (dihydroethidium staining). MMI-induced mild hypothyroidism is associated with endothelial dysfunction caused by a reduced NO availability, secondary to oxidative excess. It is suggested that in this animal model, characterized by TSH elevation and low-grade inflammation, an increased expression and function of iNOS, resulting in superoxide generation, accounts for an impaired NO availability.
- Published
- 2009
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34. Regulation of enteric functions by adenosine: pathophysiological and pharmacological implications.
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Antonioli L, Fornai M, Colucci R, Ghisu N, Tuccori M, Del Tacca M, and Blandizzi C
- Subjects
- Animals, Humans, Inflammatory Bowel Diseases metabolism, Intestines innervation, Receptors, Purinergic, Adenosine physiology, Intestinal Diseases drug therapy, Intestinal Diseases physiopathology, Intestines physiology
- Abstract
The wide distribution of ATP and adenosine receptors as well as enzymes for purine metabolism in different gut regions suggests a complex role for these mediators in the regulation of gastrointestinal functions. Studies in rodents have shown a significant involvement of adenosine in the control of intestinal secretion, motility and sensation, via activation of A1, A2A, A2B or A3 purinergic receptors, as well as the participation of ATP in the regulation of enteric functions, through the recruitment of P2X and P2Y receptors. Increasing interest is being focused on the involvement of ATP and adenosine in the pathophysiology of intestinal disorders, with particular regard for inflammatory bowel diseases (IBDs), intestinal ischemia, post-operative ileus and related dysfunctions, such as gut dysmotility, diarrhoea and abdominal discomfort/pain. Current knowledge suggests that adenosine contributes to the modulation of enteric immune and inflammatory responses, leading to anti-inflammatory actions. There is evidence supporting a role of adenosine in the alterations of enteric motor and secretory activity associated with bowel inflammation. In particular, several studies have highlighted the importance of adenosine in diarrhoea, since this nucleoside participates actively in the cross-talk between immune and epithelial cells in the presence of diarrhoeogenic stimuli. In addition, adenosine exerts complex regulatory actions on pain transmission at peripheral and spinal sites. The present review illustrates current information on the role played by adenosine in the regulation of enteric functions, under normal or pathological conditions, and discusses pharmacological interventions on adenosine pathways as novel therapeutic options for the management of gut disorders and related abdominal symptoms.
- Published
- 2008
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35. The genetics of the serotonin transporter and irritable bowel syndrome.
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Colucci R, Blandizzi C, Bellini M, Ghisu N, Tonini M, and Del Tacca M
- Subjects
- Animals, Humans, Irritable Bowel Syndrome drug therapy, Irritable Bowel Syndrome pathology, Models, Biological, Serotonin Plasma Membrane Transport Proteins physiology, Selective Serotonin Reuptake Inhibitors therapeutic use, Irritable Bowel Syndrome genetics, Polymorphism, Genetic, Serotonin Plasma Membrane Transport Proteins genetics
- Abstract
Serotonin transporter (SERT) mediates the intracellular reuptake of released serotonin, thus regulating its biological functions. Abnormalities in serotonin reuptake can alter enteric serotonergic signalling, leading to sensory, motor and secretory gut dysfunctions, which contribute to the pathophysiology of irritable bowel syndrome (IBS). This relationship has fostered the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of IBS. Current data on the efficacy of SSRIs in IBS, association of the SERT gene promoter polymorphism 5-HTTLPR with IBS and the expression pattern of SERT in the intestinal mucosa of IBS patients are conflicting. Recent molecular studies have raised critical questions about multiple SERT mRNA transcripts in the human gut, the role of polymorphic SERT promoter in the regulation of enteric SERT expression and the ability of 5-HTTLPR to affect human SERT gene transcription. The present review highlights recent advances in SERT genetics, discusses their implications for potential therapeutic applications of SSRIs in IBS and presents original suggestions for future investigations.
- Published
- 2008
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36. Effects of a bicarbonate-alkaline mineral water on digestive motility in experimental models of functional and inflammatory gastrointestinal disorders.
- Author
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Fornai M, Colucci R, Antonioli L, Ghisu N, Tuccori M, Gori G, Blandizzi C, and Del Tacca M
- Subjects
- Animals, Benzodiazepinones pharmacology, Bicarbonates administration & dosage, Colitis drug therapy, Constipation drug therapy, Diarrhea drug therapy, Disease Models, Animal, Gastric Emptying drug effects, Gastrins metabolism, Hydrogen-Ion Concentration, Male, Mineral Waters administration & dosage, Phenylurea Compounds pharmacology, Rats, Rats, Wistar, Receptors, Serotonin, 5-HT3 drug effects, Receptors, Serotonin, 5-HT3 metabolism, Bicarbonates pharmacology, Gastrointestinal Motility drug effects, Mineral Waters therapeutic use
- Abstract
This study investigates the effects of Uliveto, a bicarbonate-alkaline mineral water, in experimental models of diarrhea, constipation and colitis. Rats were allowed to drink Uliveto or oligomineral water (control) for 30 days. Diarrhea and constipation were evoked by 16,16-dimethyl-prostaglandin E(2) (dmPGE(2)) or loperamide, respectively. Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS) or acetic acid. Gastric emptying, small-intestinal and colonic transit were evaluated. dmPGE(2)-induced diarrhea reduced gastric emptying and increased small-intestinal and colonic transit. In this setting, Uliveto water enhanced gastric emptying, and this effect was prevented by L-365,260 (gastrin receptor antagonist). Loperamide-induced constipation reduced gastric emptying, small-intestinal and colonic transit, and these effects were prevented by Uliveto water. L-365,260 counteracted the effects of Uliveto on gastric emptying, while alosetron (serotonin 5-HT(3) receptor antagonist) blunted the effect of Uliveto on colonic transit. Gastric emptying, small-intestinal and colonic transit were reduced in DNBS-induced colitis, and Uliveto water enhanced gastric emptying and normalized small-intestinal and colonic transit. Gastric emptying, small-intestinal and colonic transit were also reduced in acetic acid-induced colitis, and Uliveto increased both gastric emptying and small-intestinal transit. In conclusion, Uliveto water exerts beneficial effects on gastrointestinal motility in the presence of bowel motor dysfunctions. The effects of Uliveto water on gastric emptying depend on gastrin-mediated mechanisms, whereas the activation of serotonergic pathways accounts for the modulation of colonic functions., (Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.)
- Published
- 2008
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37. Pharmacological modulation of adenosine system: novel options for treatment of inflammatory bowel diseases.
- Author
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Antonioli L, Fornai M, Colucci R, Ghisu N, Tuccori M, Del Tacca M, and Blandizzi C
- Subjects
- Animals, Enteric Nervous System physiology, Gastrointestinal Motility physiology, Humans, Immunity, Cellular physiology, Inflammation, Inflammatory Bowel Diseases drug therapy, Intestinal Mucosa metabolism, Intestines immunology, Adenosine physiology, Inflammatory Bowel Diseases physiopathology, Purinergic P1 Receptor Antagonists
- Abstract
Inflammatory bowel diseases (IBDs) are chronic disorders resulting from abnormal and persistent immune responses which lead to severe tissue injury and disturbances in digestive motor/secretory functions. At present, pharmacotherapy represents the cornerstone for the management of IBDs, and recent advances in understanding the immunopathogenesis of intestinal inflammation suggest the adenosine system as an attractive target for development of novel drugs against gut inflammatory disorders. Consistent evidence indicates that adenosine plays a relevant role in the regulation of immune system via interaction with specific cell-membrane G-protein-coupled receptors (A(1), A(2a), A(2b), and A(3)). Moreover, this nucleoside is implicated in the control of enteric neurotransmission and gut motor functions. In the presence of inflammation, the adenosine system acts as a sensible sensor apparatus, which, through dynamic modifications in the expression of ecto-enzymes and purinergic receptors, adapts its metabolism to tissue health status and contributes to the mechanisms deputed to the protection of tissues against inflammatory injuries. In keeping with these concepts, it is becoming increasingly appreciated that drugs targeted on adenosine receptors or enzymes responsible for adenosine catabolism can exert beneficial effects on experimental models of intestinal inflammation. This review aims to discuss the role of adenosine in the regulation of enteric immune responses and gut neuromuscular functions in the presence of inflammation, as well as to highlight the mechanisms through which the pharmacological modulation of adenosine pathways may have potential applications for the therapeutic management of IBDs.
- Published
- 2008
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38. Clinical efficacy of esomeprazole in the prevention and healing of gastrointestinal toxicity associated with NSAIDs in elderly patients.
- Author
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Blandizzi C, Tuccori M, Colucci R, Gori G, Fornai M, Antonioli L, Ghisu N, and Del Tacca M
- Subjects
- Age Factors, Aged, 80 and over, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Anti-Ulcer Agents adverse effects, Anti-Ulcer Agents pharmacology, Esomeprazole adverse effects, Esomeprazole pharmacology, Gastric Acid metabolism, Humans, Proton Pump Inhibitors adverse effects, Proton Pump Inhibitors pharmacology, Proton Pump Inhibitors therapeutic use, Risk Factors, Aged, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Anti-Ulcer Agents therapeutic use, Dyspepsia chemically induced, Dyspepsia prevention & control, Esomeprazole therapeutic use, Gastrointestinal Diseases chemically induced, Gastrointestinal Diseases prevention & control
- Abstract
NSAIDs are widely prescribed for the treatment of pain, inflammation and rheumatic disorders, but their use is associated with adverse gastrointestinal effects, ranging from dyspeptic symptoms and peptic ulcers to more serious complications. Elderly patients are at high risk of experiencing NSAID-induced gastrointestinal tract injury and should be considered candidates for prophylactic pharmacological therapy. In studies conducted in adult patients, proton pump inhibitors (PPIs) such as esomeprazole have been shown to prevent or reduce NSAID-induced gastrointestinal injury. The beneficial effects of esomeprazole can be ascribed largely to its ability to maintain sustained inhibition of gastric acid secretion, although there is evidence to suggest that pharmacodynamic properties unrelated to acid inhibition may also contribute to the gastroprotective effects of this agent. Although there are limited data on the use of esomeprazole specifically in elderly patient populations, studies of patients at high risk of NSAID-induced gastrointestinal toxicity because of advanced age indicate that this PPI is both effective and well tolerated when administered in conjunction with NSAIDs. Thus, esomeprazole can be regarded as a useful option for prophylactic therapy in elderly patients receiving long-term NSAID therapy.
- Published
- 2008
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39. Inhibition of adenosine deaminase attenuates inflammation in experimental colitis.
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Antonioli L, Fornai M, Colucci R, Ghisu N, Da Settimo F, Natale G, Kastsiuchenka O, Duranti E, Virdis A, Vassalle C, La Motta C, Mugnaini L, Breschi MC, Blandizzi C, and Del Taca M
- Subjects
- Adenine analogs & derivatives, Adenine chemistry, Adenine pharmacology, Adenine therapeutic use, Adenosine Deaminase chemistry, Animals, Benzenesulfonates toxicity, Body Weight drug effects, Colitis chemically induced, Colitis metabolism, Colon drug effects, Colon metabolism, Colon pathology, Cyclooxygenase 2 genetics, Dexamethasone pharmacology, Eating drug effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Gene Expression Regulation, Enzymologic drug effects, Interleukin-6 blood, Interleukin-6 metabolism, Intestinal Mucosa drug effects, Intestinal Mucosa pathology, Male, Malondialdehyde metabolism, Nitric Oxide Synthase Type II genetics, Organ Size drug effects, Peroxidase metabolism, Pyrazoles chemistry, Pyrazoles pharmacology, Pyrazoles therapeutic use, Pyrimidines chemistry, Pyrimidines pharmacology, Pyrimidines therapeutic use, Rats, Rats, Sprague-Dawley, Spleen drug effects, Spleen pathology, Tumor Necrosis Factor-alpha blood, Tumor Necrosis Factor-alpha metabolism, Adenosine Deaminase Inhibitors, Colitis drug therapy, Enzyme Inhibitors therapeutic use
- Abstract
Adenosine modulates the immune system and inhibits inflammation via reduction of cytokine biosynthesis and neutrophil functions. Drugs able to prevent adenosine catabolism could represent an innovative strategy to treat inflammatory bowel disorders. In this study, the effects of 4-amino-2-(2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine (APP; novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA; standard adenosine deaminase inhibitor), and dexamethasone were tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid (DNBS). DNBS-treated animals received APP (5, 15, or 45 micromol/kg), EHNA (10, 30, or 90 micromol/kg), or dexamethasone (0.25 micromol/kg) i.p. for 7 days starting 1 day before colitis induction. DNBS caused bowel inflammation associated with decrease in food intake and body weight. Animals treated with APP or EHNA, but not dexamethasone, displayed greater food intake and weight gain than inflamed rats. Colitis induced increment in spleen weight, which was counteracted by all test drugs. DNBS administration was followed by macroscopic and microscopic inflammatory colonic alterations, which were ameliorated by APP, EHNA, or dexamethasone. In DNBS-treated rats, colonic myeloperoxidase, malondialdehyde, and tumor necrosis factor (TNF)-alpha levels as well as plasma TNF-alpha and interleukin-6 were increased. All test drugs lowered these phlogistic indexes. Inflamed colonic tissues displayed an increment of inducible nitric-oxide synthase mRNA, which was unaffected by APP or EHNA, but reduced by dexamethasone. Cyclooxygenase-2 expression was unaffected by DNBS or test drugs. These findings indicate that 1) inhibition of adenosine deaminase results in a significant attenuation of intestinal inflammation and 2) the novel compound APP is more effective than EHNA in reducing systemic and intestinal inflammatory alterations.
- Published
- 2007
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40. CCK2 receptors mediate inhibitory effects of cholecystokinin on the motor activity of guinea-pig distal colon.
- Author
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Fornai M, Colucci R, Antonioli L, Baschiera F, Ghisu N, Tuccori M, Gori G, Blandizzi C, and Del Tacca M
- Subjects
- Adamantane analogs & derivatives, Adamantane pharmacology, Animals, Colon physiology, Devazepide pharmacology, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Electric Stimulation, Enzyme Inhibitors pharmacology, Gastrins pharmacology, Guinea Pigs, Hormone Antagonists pharmacology, Male, Muscle, Smooth drug effects, NG-Nitroarginine Methyl Ester pharmacology, Nitric Oxide Synthase Type I pharmacology, Nootropic Agents pharmacology, Perfusion, Phenylurea Compounds pharmacology, Potassium Chloride pharmacology, Receptor, Cholecystokinin B agonists, Receptor, Cholecystokinin B antagonists & inhibitors, Sincalide analogs & derivatives, Sincalide pharmacology, Cholecystokinin pharmacology, Colon drug effects, Muscle Contraction drug effects, Receptor, Cholecystokinin B physiology
- Abstract
Cholecystokinin and related peptides are involved in the control of intestinal motility and cholecystokinin receptor ligands might represent new pharmacological tools for the treatment of symptoms associated with functional bowel disorders. However, the respective roles played by cholecystokinin receptor subtypes and the mechanisms underlying these regulatory actions remain undetermined. This study was designed to examine the influence of cholecystokinin receptor subtypes on the motor activity of guinea-pig distal colon. The effects of drugs acting on CCK1 and CCK2 receptors were assessed in vitro on the contractile activity of longitudinal smooth muscle, both under basal conditions and in the presence of transmural electrical stimulation or KCl-induced contractions. The application of cholecystokinin octapeptide sulphate (cholecystokinin-8S) to colonic preparations induced concentration-dependent contractions which were prevented by devazepide (CCK1 receptor antagonist), enhanced by GV150013 (CCK2 receptor antagonist) or N(omega)-nitro-L-arginine methylester (L-NAME, nitric oxide synthase inhibitor), and unaffected by tetrodotoxin. The application of gastrin-17 to colonic preparations resulted in relaxant responses which were insensitive to devazepide, and prevented by GV150013, L-NAME or tetrodotoxin. L-NAME, N(omega)-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor) or GV150013 enhanced electrically evoked contractile responses, whereas devazepide did not. When tested in the presence of L-NAME or NPA the enhancing effect of GV150013 on electrically induced contractions no longer occurred. In the presence of KCl-induced pre-contractions, cholecystokinin-8S or gastrin-17 evoked concentration-dependent relaxations, which were unaffected by devazepide and were counteracted by GV150013, L-NAME, NPA or tetrodotoxin. In conclusion, the present results indicate that, at level of distal colon, CCK1 receptors mediate direct contractile effects on smooth muscle, whereas CCK2 receptors on enteric neurons mediate relaxant responses via nitric oxide release.
- Published
- 2007
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41. A2a receptors mediate inhibitory effects of adenosine on colonic motility in the presence of experimental colitis.
- Author
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Antonioli L, Fornai M, Colucci R, Ghisu N, Blandizzi C, and Del Tacca M
- Subjects
- Adenosine pharmacology, Animals, Disease Models, Animal, Intestinal Mucosa drug effects, Male, Muscle Contraction drug effects, Muscle Contraction physiology, Muscle, Smooth drug effects, Muscle, Smooth physiology, Nitric Oxide analysis, Nitric Oxide metabolism, Rats, Rats, Sprague-Dawley, Receptor, Adenosine A2A analysis, Reverse Transcriptase Polymerase Chain Reaction methods, Sensitivity and Specificity, Tissue Culture Techniques, Adenosine analogs & derivatives, Colitis drug therapy, Colitis pathology, Gastrointestinal Motility drug effects, Phenethylamines pharmacology, Receptor, Adenosine A2A metabolism, Triazines pharmacology, Triazoles pharmacology
- Abstract
Background: Adenosine regulates immunity and inflammation, and acts also as a modulator of gut functions. In this study, we investigated the role of adenosine A2a receptors on colonic motility in a rat model of experimental colitis., Methods: Colitis was induced by 2,4-dinitrobenzenesulfonic acid. The effects of ZM 241385 (A2a receptor antagonist) and CGS 21680 (A2a receptor agonist) were assayed on cholinergic contractions of colonic longitudinal muscle preparations evoked by transmural electrical stimulation (TES) or carbachol. A2a receptor expression in colonic neuromuscular layers was assessed by reverse transcription-polymerase chain reaction., Results: ZM 241385 increased TES-induced contractions in the absence or in the presence of colitis, the drug being more effective in colonic preparations from inflamed animals. The enhancing effects of ZM 241385 were unaffected by guanethidine or alpha-chimotrypsin, whereas being prevented by Nomega-propyl-L-arginine (neuronal nitric oxide synthase inhibitor) or adenosine 5'-(alpha,beta-methylene) diphosphate (ecto-5'-nucleotidase inhibitor). Upon exposure of colonic tissues from normal or inflamed rats to dipyridamole plus adenosine deaminase, to abate endogenous adenosine levels, CGS 21680 evoked concentration-dependent reductions of contractile responses to TES, which were more intense in preparations from inflamed rats, and were antagonized by ZM 241385. Neither CGS 21680 nor ZM 241385 affected carbachol-induced contractions. Reverse transcription-polymerase chain reaction showed an increase in A2a receptor expression in colonic tissues isolated from inflamed animals., Conclusions: The adenosine system is involved in neuroplastic changes occurring in inflamed gut. A2a receptors modulate the activity of colonic excitatory cholinergic nerves via facilitatory control on inhibitory nitrergic pathways, and such a regulatory function is enhanced in the presence of bowel inflammation.
- Published
- 2006
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