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Renga B.,University of Perugia | Mencarelli A.,University of Perugia | Cipriani S.,University of Perugia | D'Amore C.,University of Perugia | And 4 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2011

Hepatic transport and metabolism of glutamate and glutamine are regulated by intervention of several proteins. Glutamine is taken up by periportal hepatocytes and is the major source of ammonia for urea synthesis and glutamate for N-acetylglutamate (NAG) synthesis, which is catalyzed by the N-acetylglutamate synthase (NAGS). Glutamate is taken up by perivenous hepatocytes and is the main source for the synthesis of glutamine, catalyzed by glutamine synthase (GS). Accumulation of glutamate and ammonia is a common feature of chronic liver failure, but mechanism that leads to failure of the urea cycle in this setting is unknown. The Farnesoid X Receptor (FXR) is a bile acid sensor in hepatocytes. Here, we have investigated its role in the regulation of the metabolism of both glutamine and glutamate. In vitro studies in primary cultures of hepatocytes from wild type and FXR -/- mice and HepG2 cells, and in vivo studies, in FXR -/- mice as well as in a rodent model of hepatic liver failure induced by carbon tetrachloride (CCl 4), demonstrate a role for FXR in regulating this metabolism. Further on, promoter analysis studies demonstrate that both human and mouse NAGS promoters contain a putative FXRE, an ER8 sequence. EMSA, ChIP and luciferase experiments carried out to investigate the functionality of this sequence demonstrate that FXR is essential to induce the expression of NAGS. In conclusion, FXR activation regulates glutamine and glutamate metabolism and FXR ligands might have utility in the treatment of hyperammonemia states. © 2011 Elsevier B.V.

Renga B.,University of Perugia | Mencarelli A.,University of Perugia | D'Amore C.,University of Perugia | Cipriani S.,University of Perugia | And 4 more authors.
FASEB Journal | Year: 2012

The glucocorticoid receptor (GR) is a master gene orchestrating the activation of gluconeogenic genes in the liver in response to food withdrawal. Mechanisms of GR regulation by other nuclear receptors, however, are poorly defined. Here, we report that the farnesoid X receptor (FXR), a bile acid sensor, activates gluconeogenic pathways in the liver and regulates GR expression and activity. FXR-null mice are hypoglycemic in the unfed state and exhibit both a reduced hepatic production of glucose in response to the pyruvate challenge and a decreased expression of two rate-limiting enzymes involved in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), and glucose- 6-phosphatase (G6Pase), along with blunted liver expression of GR. Treating wild-type mice with a semisynthetic FXR ligand (6E-CDCA) increases the liver expression of GR, PEPCK, and G6Pase. This effect was lost in fed animals, as well as in FXR-/- mice. The human and mouse GR promoters contain a conserved FXR-responsive element (an ER-8 sequence) whose activation by FXR ligation leads to GR transcription. GR silencing by siRNA in vitro or its pharmacological antagonism in vivo with mifepristone reverses the effect of FXR activation on expression of gluconeogenic genes. These findings demonstrate that an FXR-GR pathway regulates the activation of hepatic gluconeogenesis in the transition from the unfed to the fed state. © FASEB.

Pasini F.,Ospedale S. Maria Della Misericordia | De Manzoni G.,University of Verona | Zanoni A.,University of Verona | Grandinetti A.,Radiotherapy Unit | And 5 more authors.
Cancer | Year: 2013

BACKGROUND: This phase 2 study was aimed at defining the pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, continuous infusion (c.i.) of 5-fluorouracil (5-FU) and concomitant radiotherapy (RT) in untreated stage II-III adenocarcinoma and squamous cell carcinoma of mid-distal thoracic esophagus. METHODS: The schedule consisted of a first phase of chemotherapy alone and of a second phase of concurrent chemoradiation. Doses were as follows: docetaxel 35 mg/m2 and cisplatin 25 mg/m2 on days 1, 8, 15, 29, 36, 43, 50, and 57 plus 5-FU c.i. (180 mg/m2 on days 1-21 and 150 mg/m2 on days 29-63); RT (50 Gy) started at day 29. Surgery was planned 6 to 8 weeks after the completion of chemoradiation. RESULTS: A total of 74 patients were enrolled; pathological complete remission (pCR) was found in 47% (35 of 74) and near pCR (microfoci of tumor cells on the primary tumor without lymph nodal metastases) (pnCR) in 15% of the patients (11 of 74). Grade 3-4 neutropenia, nonhematological toxicity, and toxic deaths occurred in 13.5%, 32.4%, and 4% of the patients, respectively. Median follow-up was 55 months (range, 3-108 months). Median survival of all 74 patients was 55 months, whereas it was not reached in the pCR subset. The 3- and 5-year survival rates were, respectively, 83% and 77% for pCR, 73% and 44% for pnCR, and 21% and 14% for Residual Tumor subsets (P <.001). CONCLUSIONS: This study shows that 1) this intensive weekly schedule produced a high pathological response rate, 2) responders had high and long-term durable survival rates. Cancer 2013. © 2012 American Cancer Society. This phase 2 study sought to define the pathological response rate of a neoadjuvant schedule including weekly docetaxel and cisplatin, continuous infusion of fluorouracil, and concomitant radiotherapy in untreated stage II-III adenocarcinoma and squamous cell carcinoma of mid-distal thoracic esophagus. Results show that this intensive weekly schedule produced a high pathological response rate, and responders had high and long-term durable survival rates. Copyright © 2012 American Cancer Society.

Buiatti A.,University of Trieste | Merlo M.,University of Trieste | Pinamonti B.,University of Trieste | De Biasio M.,Ospedale S. Maria Della Misericordia | And 2 more authors.
Journal of Cardiovascular Medicine | Year: 2013

BACKGROUND: The natural history of perimyocarditis (PMY) is not yet completely known. We aimed to analyse the clinical laboratory data of PMY at diagnosis and during follow-up, in order to assess the natural history and prognostic stratification of the disease (including different aetiology). METHODS: We enrolled 62 consecutive patients (men 79%, aged 38±18 years) with PMY (84% idiopathic, 8% autoimmune, 8% infective) from August 2002 to July 2010. The diagnosis has been made according to clinical and laboratory data (significant increase of troponin I in all patients). After at least 1 year (mean follow-up: 1635±298 days), 59 patients (95%) had available data. RESULTS: Chest pain was present in 59 patients (95%), flu-like syndrome in 36 (58%) and pericardial rubs in 15 (24%). None of the patients showed heart failure at presentation. At admission, eight patients (13%) presented mild-moderate left ventricular systolic dysfunction, 13 (22%) showed wall motion abnormalities, and 10 (17%) showed mild pericardial effusion. At 1 year no patients died, developed heart failure or showed abnormal echocardiogram. NSAIDs were the first choice therapy in 61 (98%) patients with clinical resolution in 58 (95%) of them. Seven patients (12%) experienced intermittent recurrences without development of constrictive pericarditis or heart failure. CONCLUSION: This study underlines the benign mid- to long-term outcome of PMY regardless of clinical laboratory characteristics at presentation, different aetiology and possibility of relapses; minimizing the role of endomyocardial biopsy in these specific patients. Copyright © 2013 Italian Federation of Cardiology.

Santini M.,Ospedale S. Filippo Neri | Lunati M.,Ospedale Niguarda Ca Granda | Mermi J.,Klinikum Dortmund | Proclemer A.,Ospedale S. Maria Della Misericordia | And 6 more authors.
Journal of Interventional Cardiac Electrophysiology | Year: 2010

Purpose The purpose of the trial was to quantify and compare the efficacy of two different sequences of burst anti-tachycardia pacing (ATP) strategies for the termination of fast ventricular tachycardia. Methods The trial was prospective, multicenter, parallel and randomized, enrolling patients with an indication for implantable cardioverter-defibrillator implantation. Results From February 2004, 925 patients were randomized and followed-up for 12 months. Eight pulses ATP terminated 64% of episodes vs. 70% in the 15-pulse group (p=0.504). Fifteen pulses proved significantly better in patients without a previous history of heart failure (p=0.014) and in patients with LVEF>40% (p=0.016). No significant differences between groups were observed with regard to syncope/ near-syncope occurrence. Conclusion In the general population, 15-pulse ATP is as effective and safe as eight-pulse ATP. The efficacy of ATP on fast ventricular arrhythmias confirmed once more the striking importance of careful device programming in order to reduce painful shocks. © The Author(s) 2010.

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