17,207,968 research outputs found
Neuropeptide Y inhibits forskolin-stimulated adenylate cyclase activity in rat hippocampus. Petrenko S, Olianas MC, Onali P, Gessa GL.
No full textNeuropeptide Y inhibited the forskolin-stimulated adenylate cyclase activity in rat hippocampus with the half-maximal effect occurring at 73 nM. The maximal inhibition corresponded to a 17-22% decrease of the control level of enzyme activity. The effect of neuropeptide Y was mimicked by the peptide YY but not by the avian pancreatic polypeptide and required micromolar concentrations of GTP. These results indicate that, in the brain, the inhibition of adenylate cyclase activity constitutes a mechanism by which the receptor for neuropeptide Y transduces its signal
Postoperative Crohn's disease recurrence as assessed by conventional vs alternative non invasive techniques
No full textBackground Ileocolonoscopy (IC) is the gold standard for assessing Crohn’s Disease (CD) recurrence after ileo-colonic resection The frequency of recurrence in Crohn’s CD patients after curative resection different from the ileo-colonic is undefined.
Aims. Prospective Study: We aimed to compare, in a prospective longitudinal study, findings related to CD recurrence as assessed by procedures visualizing either the luminal surface (i.e. ileocolonoscopy or SBFT) or the extraluminal surface (SICUS) in a cohort of CD patients prospectively followed up at 1, 2 and 3 years after ileo-colonic resection.
Retrospective Study:In an different cohort of CD patients, we also aimed to assess, in retrospective analysis, the frequency, pattern and risk factors of postoperative recurrence in CD patients with “curative” resection different from ileo-colon.
Methods. Prospective Study: From 2003 to 2008, 25 CD patients undergoing ileo-colonic resection were enrolled. Clinical assessment (CDAI) was performed at 1, 2 and 3 years. IC was performed at 1 (n=25) and 3 years (n=15), SBFT at 2 years (n=21) and SICUS at 1 (n=25), 2 (n=21) and 3 years (n=15). Recurrence was assessed by SBFT and SICUS (bowel wall thickness, BWT) when using IC as gold standard. Retrospective Study: In a retrospective study, clinical records of 537 CD patients under regular follow up from January 2001 to August 2007 were reviewed. The outcome after surgery was assessed on the basis of clinical records prospectively recorded.
Results. Prospective Study: At 1 year, all patients were inactive and recurrence was detected by IC in 24/25 (96%) and by SICUS in 25/25 patients. At 2 years, 6/21 patients (29%) were active and recurrence was detected by SBFT in 12/21 (57%) and by SICUS in 21/21 patients. At 3 years, 5/15 patients (33%) were active, IC showed recurrence in 14/15 (93%), and SICUS in 15/15 patients. The endoscopic score at 1 year was higher in patients developing relapse at 2 years (n=5) than in patients maintaining remission (n=10)(median: 4, range 3-4 vs 2, range 0-3; p=0.003). The same finding was not observed by using SICUS (median BWT at 1 year: 5, range 4-7 vs 3.7, range 3.5-6; p=0.19).
Retrospective Study Previous resection was observed in 183/537 (34%) patients, including the ileo-colon in 145 (79%) and other GI segments in 38 (21%). Recurrence was detected in 16/38 (42%) patients (all symptomatic) including: 5/14 (35%) with ileostomy, 5/5 (100%) with ileo-rectal, 3/11 (27%) with ileo-ileal, 1/4 (25%) with colo-rectal and 2/3 (33%) with duodenum-jejunal anastomosis. Ileo-colonic resection was reported in 145/183 (79%) patients, showing recurrence in 128 (88.3%), symptomatic in 47 (36.7%) patients. The frequency of recurrence was higher in patients with ileo-colonic resection than in patients with other types of resection (128/145, 88% vs 16/38, 42%, p<0.001). The frequency of symptomatic recurrence was lower in patients with ileo-colonic resection than in those with other resections (47/128, 37% vs 16/16, 100%; p<0.001). Risk factors for recurrence were comparable in the 2 subgroups (smoke: OR 1.5 vs 1.4; appendectomy: OR 0.32 vs 0.33; familial IBD: OR 0.43 vs 1.26
Conclusions. Although IC and SICUS provide a different view of the bowel wall, in experienced hands SICUS provides findings compatible with endoscopic recurrence after ileo-colonic resection for CD. Post-operative recurrence is observed in a high proportion of CD patients after resection different from ileo-colon (including ileostomy), although out a lower frequency than observed after ileo-colonic resectio
Evidence that the GABAB positive allosteric modulator CGP7930 activates MAPK cascade independently of GABAB receptor
No full textThe GABAB positive allosteric modulator (PAM) CGP7930 potentiates GABAB receptor signaling in transfected cells (Urwyler et al. Mol. Pharmacol. 60, 963971, 2001) and rat and human brain (Onali et al., Eur. J. Pharmacol. 471, 7784, 2003; Olianas et al., Neurochem. Int. 46, 149158, 2005). A number of behavioral studies have also shown that CGP7930 exerts anxiolytic effects and reduces selfadministration of drugs of abuse (Adams and Lawrence, CNS Drug Rev. 13, 308316, 2007). However, little is known on whether this drug can affect neuronal signaling independently of GABAB receptor activity. In the present study we report that in human SHSY5Y neuroblastoma cells, CGP7930 (30 μM) induced a rapid increase of dual phosphorylation (activation) of ERK1/2, which reached a maximum at 15 min and lasted for at least 60 min. CGP7930 also triggered CREB phosphorylation at Ser133 with a similar kinetic profile. Under the same experimental conditions, the GABAB receptor agonist () baclofen (100 μM) failed to affect ERK1/2 phosphorylation, and when combined with CGP7930, it did not elicit any further ERK1/2 stimulation. CGP7930induced ERK1/2 phosphorylation was not prevented by cell pretreatment with either the GABAB receptor antagonists CGP55845A and CGP54626, the Gi/oreceptor uncoupler pertussis toxin, the Gq/11 antagonist YM254890, or the tyrosine kinase inhibitor genistein. Conversely, it was completely blocked by the MEK inhibitor PD98059 and significantly attenuated by the protein kinase C inhibitors Go 6983 and bisindolylmaleimide I. CGP7930 (30 μM) was also found to stimulate ERK1/2 phosphorylation in CHOK1 cells, which do not express GABAB receptors. However, CGP7930 (1100 μM) had no effect in HEK293 cells, indicating that ERK1/2 activation was not a generalized cellular response to the PAM. These data indicate that CGP7930 can affect ERK1/2 signaling, which is known to be involved in the control of mood and drug addiction, independently of increased GABAB receptor activity
Antidepressants induce profibrotic responses via the lysophosphatidic acid receptor LPA1
No full textPreclinical and clinical studies have indicated that antidepressants can promote inflammation and fibrogenesis, particularly in the lung, by mechanisms not fully elucidated. We have previously shown that different classes of antidepressants can activate the lysophosphatidic acid (LPA) receptor LPA1, a major pathogenetic mediator of tissue fibrosis. The aim of the present study was to investigate whether in cultured human dermal and lung fibroblasts antidepressants could trigger LPA1-mediated profibrotic responses. In both cell types amitriptyline, clomipramine and mianserin mimicked the ability of LPA to induce the phosphorylation/activation of extracellular signal –regulated kinases 1 and 2 (ERK1/2), which was blocked by the selective LPA1 receptor antagonist AM966 and the LPA1/3 antagonist Ki16425. Antidepressant-induced ERK1/2 stimulation was absent in fibroblasts stably depleted of LPA1 by short hairpin RNA transfection and was prevented by pertussis toxin, an uncoupler of receptors from Gi/o proteins. Like LPA, antidepressants stimulated fibroblasts proliferation and this effect was blocked by either AM966 or the MEK1/2 inhibitor PD98059. Moreover, by acting through LPA1 antidepressants induced the expression of α-smooth muscle actin (α-SMA), a marker of myofibroblast differentiation, and caused an ERK1/2-dependent increase in the cellular levels of transforming growth factor-β (TGF-β)1, a potent fibrogenic cytokine. Pharmacological blockade of TGF-β receptor type 1 prevented antidepressant- and LPA-induced α-SMA expression. These data indicate that in human dermal and lung fibroblasts different antidepressants can induce proliferative and differentiating responses by activating the LPA1 receptor coupled to ERK1/2 signalling and suggest that this property may contribute to the promotion of tissue fibrosis by these drugs
Inhibition of TNF-α-induced neuronal apoptosis by antidepressants acting through the lysophosphatidic acid receptor LPA1
No full textTumor necrosis factor- (TNF-), a pro-inflammatory cytokine considered to be implicated in the pathogenesis of major depressive disorder, is a critical regulator of neuronal cell fate. In the present study we found that TNF--induced apoptosis of HT22 hippocampal cells, a neuroblast-like cell line, was markedly attenuated by the antidepressants mianserin, mirtazapine and amitriptyline. The anti-apoptotic effect of the antidepressants was blocked by either pharmacological inhibition or gene silencing of the lysophosphatidic acid receptor LPA(1). Mianserin failed to affect TNF--induced caspase 8 activation, but inhibited the loss of mitochondrial membrane potential, the release of cytochrome c from mitochondria, procaspase 9 cleavage and downstream activation of caspase 3 in response to the cytokine. By acting through LPA(1), mianserin also attenuated the enhanced pro-apoptotic response induced by the combination of TNF- with other pro-inflammatory cytokines. TNF- appeared to counterbalance its own pro-apoptotic response by activating NF-kB, ERK1/2 and JNK. Antidepressants had no significant effects on NF-kB activation, but potentiated the TAK-1-dependent phosphorylation of ERK1/2 and JNK elicited by the cytokine. This synergistic interaction was associated with enhanced JNK-mediated phosphorylation of Bcl-2at Ser70 and increased ERK1/2-dependent mitochondrial accumulation of Mcl-1, two anti-apoptotic proteins that promote mitochondrial outer membrane stability. These results indicate that certain antidepressants, by activating LPA(1) signalling, protect HT22 hippocampal cells from TNF--induced apoptosis through a mechanism involving, at least in part, the potentiation of the pro-survival pathways activated by the cytokine
Measuring disease activity in Crohn's disease
No full textIn the last few years the management of Crohn's disease (CD) has changed due to the introduction of new therapeutic agents that provide more alternative options in patients with severe diseases, introducing new concepts regarding treatment timing. At the moment, the absence of good predictors of disease outcome and a subclinical marker available to predict relapse during clinical remission are major problems in the management of CD. In recent decades, the evaluation of several variables has been proposed to address this issue, including disease behavior, clinical-endoscopic activity and intestinal damage. In particular, definition of mucosal restitution or healing after therapy has been proposed as a surrogate of efficacy and new goal of the therapy. Regarding this concept, several criticisms have been raised, such as the need to better define the role of mucosal healing in a transmural disease. In order to address this issue, new alternative techniques providing both extraluminal and luminal intestinal damage have been proposed, including ultrasonography, computed tomography and magnetic resonance imaging
Measuring disease activity in Crohn's disease
No full textIn the last few years the management of Crohn's disease (CD) has changed due to the introduction of new therapeutic agents that provide more alternative options in patients with severe diseases, introducing new concepts regarding treatment timing. At the moment, the absence of good predictors of disease outcome and a subclinical marker available to predict relapse during clinical remission are major problems in the management of CD. In recent decades, the evaluation of several variables has been proposed to address this issue, including disease behavior, clinical-endoscopic activity and intestinal damage. In particular, definition of mucosal restitution or healing after therapy has been proposed as a surrogate of efficacy and new goal of the therapy. Regarding this concept, several criticisms have been raised, such as the need to better define the role of mucosal healing in a transmural disease. In order to address this issue, new alternative techniques providing both extraluminal and luminal intestinal damage have been proposed, including ultrasonography, computed tomography and magnetic resonance imaging. © 2012 Springer Science+Business Media, LLC
Antagonism by (R)- and (S)-trihexyphenidyl of muscarinic stimulation of adenylyl cyclase in rat olfactory bulb and inhibition in striatum and heart
No full text1. Activation of muscarinic receptors in rat olfactory bulb stimulates adenylyl cyclase activity. This response was competitively antagonized by the (R)- and (S)-enantiomers of trihexyphenidyl with pA2 values of 8.84 and 6.09, respectively. 2. Similarly, in rat striatal homogenates, muscarinic inhibition of adenylyl cyclase activity was antagonized by the (R)- and (S)-enantiomers with pA2 values of 8.75 and 6.12, respectively. 3. In contrast, in rat myocardium the muscarinic inhibition of the adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation was more weakly antagonized by trihexyphenidyl, with a particularly marked loss (15 fold) in activity of the (R)-enantiomer. The (R)- and (S)-enantiomers had pA2 values of 7.64 and 5.72, respectively. 4. Each muscarinic response was completely antagonized by increasing concentrations of (R)-trihexyphenidyl with a Hill coefficient not significantly different from unity. 5. The present study shows that the muscarinic receptors coupled to stimulation of adenylyl cyclase in the olfactory bulb display high stereoselectivity for the enantiomers of trihexyphenidyl. The affinities of these receptors for the antagonists are similar to those shown by the striatal receptors. This finding supports the hypothesis that both the muscarinic stimulation of adenylyl cyclase in the olfactory bulb and the muscarinic inhibition of the enzyme in striatum are mediated by activation of a receptor subtype pharmacologically equivalent to the m4 gene product. On the other hand, the weaker affinities and the lower stereoselectivity for the trihexyphenidyl enantiomers exhibited by the muscarinic inhibition of adenylyl cyclase in the heart are consistent with the involvement of M2 receptors in this response
- …
