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41.
42.
Biagi G Giorgi I Leonardi M Livi O Pacchini F Scartoni V Costa B Lucacchini A 《European journal of medicinal chemistry》2003,38(9):801-810
In this paper we describe synthesis and biological assays of some A(1) ligands more water-soluble than the effective, but very lipophilic, 8-azaadenines and adenines discovered in the past and obtained introducing on N(6) or N(9) substituent a hydroxy group. Five of the new N(6)-hydroxyalkyl- and N(6)-hydroxycycloalkyl-2-phenyl-9-benzyl-8-azaadenines showed very high affinity (Ki<40 nM) and selectivity for A(1) adenosine receptors. Among the 2-phenyl-9-(2-hydroxy-3-alkyl)-8-azaadenines or adenines prepared, the compounds with the higher A(1) affinity and selectivity resulted 2-phenyl-9-(2-hydroxy-3-propyl)-N(6)-cyclopentyl- and cyclohexyl-8-azaadenine with Ki 2.2+/-0.2 nM and 2.8+/-0.3 nM respectively. From the point of view of water-solubility, 2-phenyl-9-(2-hydroxy-3-propyl)-8-azaadenine was the most interesting compound, having a CLogP of 1.066991 and a water-solubility of 1.2 mg mL(-1). 相似文献
43.
Anastasi S Fiorentino L Fiorini M Fraioli R Sala G Castellani L Alemà S Alimandi M Segatto O 《Oncogene》2003,22(27):4221-4234
The ErbB-2 interacting protein receptor-associated late transducer (RALT) was previously identified as a feedback inhibitor of ErbB-2 mitogenic signals. We now report that RALT binds to ligand-activated epidermal growth factor receptor (EGFR), ErbB-4 and ErbB-2.ErbB-3 dimers. When ectopically expressed in 32D cells reconstituted with the above ErbB receptor tyrosine kinases (RTKs) RALT behaved as a pan-ErbB inhibitor. Importantly, when tested in either cell proliferation assays or biochemical experiments measuring activation of ERK and AKT, RALT affected the signalling activity of distinct ErbB dimers with different relative potencies. RALT deltaEBR, a mutant unable to bind to ErbB RTKs, did not inhibit ErbB-dependent activation of ERK and AKT, consistent with RALT exerting its suppressive activity towards these pathways at a receptor-proximal level. Remarkably, RALT deltaEBR retained the ability to suppress largely the proliferative activity of ErbB-2.ErbB-3 dimers over a wide range of ligand concentrations, indicating that RALT can intercept ErbB-2.ErbB-3 mitogenic signals also at a receptor-distal level. A suppressive function of RALT deltaEBR towards the mitogenic activity of EGFR and ErbB-4 was detected at low levels of receptor occupancy, but was completely overcome by saturating concentrations of ligand. We propose that quantitative and qualitative aspects of RALT signalling concur in defining identity, strength and duration of signals generated by the ErbB network. 相似文献
44.
A Sapone L Pozzetti D Canistro M Broccoli G Bronzetti G Potenza A Affatato G L Biagi G Cantelli-Forti M Paolini 《Food and chemical toxicology》2005,43(1):173-183
This work aimed to investigate whether the insecticide acephate (125 or 250 mg/kg b.w.) or diflubenzuron (752 or 1075 mg/kg b.w.), two of the most widely used pesticides worldwide, impairs CYP-linked murine metabolism in liver, kidney and lung microsomes after repeated (daily, for three consecutive days) i.p. administration. The regio- and stereo-selective hydroxylation of testosterone was used as multibiomarker of different CYP isoforms. Both gender and tissue specific effects were observed. Lung was the most responsive tissue to induction by lower diflubenzuron dose, as exemplified by the marked increase of testosterone 7alpha-hydroxylation (CYP2A) (up to 13-fold) in males. Higher dose produced a generalized inactivation. At the lower dose acephate induced 6beta- (CYP3A1/2, liver) as well as 2beta- (CYP2B1/2, kidney) hydroxylase activities ( approximately 5 and approximately 4-fold increase, respectively) in males. In females, a marked suppression of the various hydroxylations was observed. At 250 mg/kg of acephate, animals did not survive. Induction of the most affected isoforms was sustained by immunoblotting analysis. Corresponding human CYP modulations might disrupt normal physiological functions related to these enzymes. Furthermore, the co-mutagenic and promoting potential of these pesticides, phenomena linked to CYP upregulation (e.g. increased bioactivation of ubiquitous pollutants and generation of oxygen free radicals) are of concern for a more complete definition of their overall toxicological potential. 相似文献
45.
Julyan H.E. Cartwright Nicolas Piro Oreste Piro Idan Tuval 《Developmental dynamics》2008,237(12):3477-3490
The manner in which the nodal flow determines the breaking of left–right symmetry during development is a beautiful example of the application of fluid dynamics to developmental biology. Detailed understanding of this crucial developmental process has greatly advanced by the transfer of ideas between these two disciplines. In this article, we review our and others' work on applying fluid dynamics and dynamical systems to the problem of left–right symmetry breaking in vertebrates. Developmental Dynamics 237:3477–3490, 2008. © 2008 Wiley‐Liss, Inc. 相似文献
46.
Elevated plasma total homocysteine in centenarians. 总被引:1,自引:0,他引:1
Mariano Malaguarnera Giovanni Pistone Massimo Motta Ernesto Vinci Giovanni Oreste Gino Avellone Salvatore Musumeci 《Clinical chemistry and laboratory medicine》2004,42(3):307-310
Homocysteine (Hcy) is a sulfur-containing metabolite of methionine and is an emerging independent risk factor for atherosclerosis. Previous studies have shown that age, gender, renal function and folic acid intake are the main factors influencing total plasma Hcy levels in humans. A unique approach to the science of human longevity is the natural model of centenarians. The objective of this study was to verify whether the previously determined risk factors for atherosclerosis and atherosclerosis-related diseases change with age and, finally, to establish the vitamin nutritional status role. We studied 54 centenarians (14 males and 40 females) aged between 100-107 years (mean age 102.6+/-1.8 years) living in Sicily (Italy), recruited via the Registry Office, and compared them with three control groups composed of subjects with different age ranges. Total plasma Hcy, folate, vitamin B12 and pyridoxal phosphate (PLP) levels were compared between the groups by the Student's t test. The comparison between centenarians and <65-year old, randomly selected individuals showed that in centenarians the mean value of serum creatinine levels was 18 micromol/l (p=0.000) higher, the mean total Hcy value was 22 micromol/l higher (p=0.000), the mean PLP value was 17.9 nmol/l lower (p=0.000), the mean folate level was 2.1 nmol/l lower (p<0.001) and vitamin B12 was 70.5 pmol/l lower (p=0.000). The comparison between centenarians and >65-year old, randomly selected individuals showed that in centenarians the mean value of serum creatinine levels was 8 micromol/l higher (p=0.037), the mean total Hcy value was 11.6 micromol/l higher (p=0.000) and the mean PLP value was 4.2 nmol/l higher (p=0.000). It seems that centenarians are protected by some mechanism (maybe genetic) that allows them a long survival despite the high value of homocysteinemia. On the other hand, it can by hypothesized that good vitamin intake is essential to live over 100 years. 相似文献
47.
Fabrizio Cardin Nadia Minicuci Alessandra Andreotti Elena Pinetti Federico Campigotto Barbara M Donà Bruno Martella Oreste Terranova 《BMC gastroenterology》2010,10(1):123
Background
Achieving the target of 95% colonoscopy completion rate at centres conducting colorectal screening programs is an important issue. Large centres and teaching hospitals employing endoscopists with different levels of training and expertise risk achieving worse results. Deep sedation with propofol in routine colonoscopy could maximize the results of cecal intubation. 相似文献48.
Paolo Sorrentino Luigi Terracciano Salvatore D’Angelo Umberto Ferbo Alessandra Bracigliano Luciano Tarantino Alessandro Perrella Oreste Perrella Giovanni De Chiara Luigi Panico Noè De Stefano Mariolina Lepore Raffaela Vecchione 《Journal of gastroenterology》2010,45(10):1053-1062
Background
Factors responsible for the progression of primary biliary cirrhosis (PBC) are still poorly understood. In the present study, we investigated the associations between the stage of PBC and the immune reaction triggered by oxidative stress; the presence of obesity, steatosis, steatohepatitis; and other toxic, metabolic, or steatogenic factors.Methods
We studied clinical, laboratory, and histological data for 274 untreated patients with serum antimitochondrial antibody (AMA)-positive PBC. Circulating IgG against human serum albumin adducted with malondialdeyde, the major product of lipid peroxidation, was measured in these patients and in a group of 98 sex-, age- and body mass index (BMI)-matched controls.Results
Steatosis was present in 40.5% of all patients. Steatohepatitis was present in 14.9% of all patients. There was a significant association between the frequencies of steatosis and steatohepatitis and the worsening of PBC. Circulating IgG against lipid peroxidation products was significantly higher in the PBC patients than in the controls. Titers of lipid peroxidation-related antibodies were significantly increased in patients with steatosis and in patients at more advanced stages. Bivariate analysis revealed a significant association between indirect evidence of oxidative stress, steatosis, steatohepatitis, age, BMI, frequency of diabetes, alcohol intake, iron grade after Perl’s stain, and PBC stage. Logistic regression analysis confirmed that the titers of antibodies against lipid peroxidation products (odds ratio 4.5, p < .001, 95% confidence interval 3.9–14.4), the presence of steatosis (odds ratio 4.1, 95% confidence interval 2.5–15.4, p < .001), higher BMI (odds ratio 3.9, p < .021, 95% confidence interval 1.4–9.5), and alcohol intake (males ≥ 30 g/day, females ≥ 20 g/day, odds ratio 4.5, 95% confidence interval 1.3–19.8, p < .029) were independently associated with more advanced stages of the disease.Conclusions
The immune reactions triggered by oxidative stress, steatosis, obesity, and alcohol intake are independent predictors of PBC stage progression. 相似文献49.
Manes G Ardizzone S Lombardi G Uomo G Pieramico O Porro GB 《Gastrointestinal endoscopy》2007,65(7):982-987
BACKGROUND AND OBJECTIVE: Gabexate mesylate reduces the incidence of post-ERCP pancreatitis. Patient-related risk factors associated with pancreatitis can be identified before ERCP, but the procedure-related factors are recognized only at the end of the procedure. This study's aim was to evaluate whether gabexate mesylate administered after ERCP reduces the incidence of pancreatitis. DESIGN: Randomized, prospective, double-blind, multicenter trial. SETTING: Tertiary care centers. PATIENTS AND INTERVENTION: A total of 608 patients undergoing ERCP were treated with gabexate mesylate 500 mg within 1 hour before ERCP (group A, 203 patients) or within 1 hour after ERCP (group B, 203), or with saline solution (group C, 202). MAIN OUTCOME MEASUREMENTS: The incidence and severity of pancreatitis and hyperamylasemia, as well as factors associated with the development of pancreatitis. RESULTS: The groups were similar for demographic characteristics, indications to ERCP, risk factors for pancreatitis, and therapeutic procedures. The incidence of pancreatitis was 3.9% in group A, 3.4% in group B, and 9.4% in group C (P<.01). Two patients (in groups A and C) developed necrotizing pancreatitis, and 1 died. Hyperamylasemia occurred in 23.6% in groups A and B, and in 24.7% in group C. Levels of amylase, the incidence of abdominal pain, and other complications occurred similarly. Female sex (odds ratios [OR] 2.7, 95% CI 1.2-5.9) and difficult cannulation (OR 5.6, 95% CI 2.6-12.3) were independently associated with pancreatitis. CONCLUSIONS: The administration of gabexate mesylate after ERCP protects against the development of pancreatitis similarly to the preprocedure administration. Factors associated with pancreatitis were mainly recognized after ERCP. We suggest administering gabexate mesylate after ERCP only in those patients recognized to be at risk of developing pancreatitis. 相似文献
50.
Galderisi M de Simone G Innelli P Turco A Turco S Capaldo B Riccardi G de Divitiis O 《American journal of hypertension》2007,20(5):548-555
BACKGROUND: Left ventricular (LV) concentric geometry and hypertrophy, depressed wall mechanics, and abnormal diastolic properties have been described in the diabetic heart. However, the cardiac response to dynamic exercise in diabetic patients remains controversial. The present study assessed strain rate (SR) imaging during dobutamine stress, to investigate inotropic response in patients with type 2 diabetes mellitus and without coronary artery disease. METHODS: Twenty-four diabetics and 16 controls, both free of coronary artery disease, underwent Doppler echocardiography at rest and during dobutamine stress. Tissue Doppler systolic (S(m)) and early diastolic (E(m)) velocities, SR, and strain of middle posterior septum were measured at rest, low-dose, and high-dose dobutamine. RESULTS: Diabetics had higher LV mass and relative wall thickness, lower midwall shortening, and transmitral pattern of abnormal LV relaxation. At rest, E(m) was significantly lower but S(m), SR, and strain were similar between the two groups. At low-dose and high-dose dobutamine, without difference of S(m), SR and strain were significantly lower in diabetics. At every level of dobutamine, strain increased with increasing heart rate (HR) in either group (both P < .0001), but the slope of the overall relation between HR and strain was lower in diabetics (b = -0.08) than in controls (b = -0.14) (P < .01). CONCLUSIONS: In type 2 diabetes SR imaging allows detection of reduced longitudinal mechanics during dobutamine stress. The blunted slope of the relation between HR and regional strain suggests the impairment of the myocardial force-frequency relation, indicating altered contractile reserve in uncomplicated diabetes. 相似文献