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Belghiti M.,Research Center Principe Felipe | Agusti A.,Institute Investigacion Sanitaria INCLIVA | Hernandez-Rabaza V.,Research Center Principe Felipe | Cabrera-Pastor A.,Research Center Principe Felipe | And 2 more authors.
Neurochemical Research | Year: 2016

Pruritus is a common symptom in chronic liver diseases, which may also alter thermal sensitivity. The underlying mechanisms remain unclear and treatments are not satisfactory. Portal-systemic shunting has been proposed to alter thermal sensitivity in cirrhotics. Inflammation-induced enhanced activity of the Transient Receptor Potential Vanilloid 1 (TRPV1) may contribute to pruritus and thermal hyperalgesia. Sildenafil reduces neuroinflammation in portacaval shunt (PCS) rats. The aims were to assess whether: (1) PCS rats show enhanced scratching or thermal sensitivity; (2) TRPV1 activity is enhanced in PCS rats; (3) treatment with sildenafil reduces TRPV1 activation, scratching and thermal hyperalgesia. Rats were treated with sildenafil beginning 3 weeks after surgery. The number of scratches performed were counted. Thermal hyperalgesia was analyzed using the Hargreaves’ Plantar Test. TRPV1 activation by measuring the increase in Ca2+ induced by capsaicin in dorsal root ganglia neurons. PCS rats show enhanced scratching behavior, reaching 66 ± 5 scratches/h (p < 0.01) at 21 days after surgery, while controls show 37 ± 2 scratches/h. PCS rats show thermal hyperalgesia. Paw withdrawal latency was reduced (p < 0.05) to 10 ± 1 s compared to controls (21 ± 2 s). Capsaicin-induced calcium increase was higher in dorsal root ganglia cultures from PCS rats, indicating TRPV1functional increase. PCS rats show enhanced scratching behavior and thermal sensitivity and are a good model to study these alterations in chronic liver diseases. Enhanced sensitivity and activity of TRPV1 channel underlies these alterations. Treatment with sildenafil reduces TRPV1 channel sensitivity and activity and normalizes scratching behavior and thermal sensitivity. © 2016 Springer Science+Business Media New York Source

Gomez-Navarro N.,University of Valencia | Peiro-Chova L.,University of Valencia | Peiro-Chova L.,Institute Investigacion Sanitaria INCLIVA | Rodriguez-Navarro S.,Research Center Principe Felipe | And 2 more authors.
Molecular and Cellular Biology | Year: 2013

The assembly and nuclear transport of RNA polymerase II (RNA pol II) are processes that require the participation of many auxiliary factors. In a yeast genetic screen, we identified a previously uncharacterized gene, YMR185w (renamed RTP1), which encodes a protein required for the nuclear import of RNA pol II. Using protein affinity purification coupled to mass spectrometry, we identified interactions between Rtp1p and members of the R2TP complex. Rtp1p also interacts, to a different extent, with several RNA pol II subunits. The pattern of interactions is compatible with a role for Rtp1p as an assembly factor that participates in the formation of the Rpb2/Rpb3 subassembly complex and its binding to the Rpb1p-containing subcomplex. Besides, Rtp1p has a molecular architecture characteristic of karyopherins, composed of HEAT repeats, and is able to interact with phenylalanine- glycine-containing nucleoporins. Our results define Rtp1p as a new component of the RNA pol II biogenesis machinery that plays roles in ubunit assembly and likely in transport through the nuclear pore complex. © 2013, American Society for Microbiology. Source

Rodriguez-Berna G.,Polytechnic University of Valencia | Mangas-Sanjuan V.,University Miguel Hernandez | Gonzalez-Alvarez M.,University Miguel Hernandez | Gonzalez-Alvarez I.,University Miguel Hernandez | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2014

Oral administration of camptothecin (CPT) derivatives and other antitumoral agents is being actively developed in order to improve the quality of life of patients with cancer. Though several lipophilic derivatives of CPT have shown interesting oral bioavailability in preclinical and clinical studies, only Topotecan has been approved for this route of administration. Semisynthesis, antitumor activity, biological inhibition mechanism, and in situ intestinal permeability of 9, 10-[1,3]-Dioxinocamptothecin (CDiox), an unexplored CPT derivative, have been studied in this paper. The hexacyclic analog was as effective as Topotecan and CPT in different tumor cell lines, showing an expected similar apoptosis cell mechanism and high ability to inhibit DNA synthesis in HeLa, Caco-2, A375 and MDA-MB-231 cell lines. Furthermore, in vitro and in situ pharmacokinetics transport values obtained for CDiox displayed more favorable absorption profile than CPT and Topotecan. © 2014 Elsevier Masson SAS. All rights reserved. Source

Ampuero J.,University of Seville | Simon M.,Hospital Universitari Vall dHebron | Montoliu C.,Institute Investigacion Sanitaria INCLIVA | Jover R.,Hospital General Universitario | And 3 more authors.
Gastroenterology | Year: 2015

Background and Aims Minimal hepatic encephalopathy (MHE) is associated with falls, traffic accidents, and overt HE. However, the association with survival is controversial. We assessed the effects of MHE on the long-term survival of patients with cirrhosis. Methods We performed a prospective study of 117 consecutive patients with cirrhosis seen at a tertiary hospital in Seville, Spain (estimation cohort), followed by a validation study of 114 consecutive patients with cirrhosis seen at 4 hospitals in Spain from January 2004 through December 2007. Patients were examined every 6 months at outpatient clinics through December 2013 (follow-up periods of 5 ± 2.8 y and 4.4 ± 3.9 y for each group, respectively). Cirrhosis was identified by liver biopsy, ultrasound, endoscopic analysis, and biochemical parameters. Liver dysfunction was determined based on model for end-stage liver disease (MELD) and Child-Pugh scores. All patients were administered the critical flicker frequency (CFF) test and psychometric hepatic encephalopathy scores were used to detect MHE. Survival curves were compared using the log-rank test and multivariable analysis was performed using Cox proportional hazards models. Results The distributions of Child-Pugh scores were as follows: 66% class A, 31% class B, and 3% class C in the estimation cohort, and 50% class A, 32% class B, and 18% class C in the validation cohort. In the estimation cohort, 24 of 35 patients (68.6%) with a CFF score less than 39 Hz survived for 5 years, whereas 50 of 61 patients (82%) with a CFF score of 39 Hz or higher survived during the follow-up period (log-rank score, 5.07; P =.024). Psychometric hepatic encephalopathy scores did not correlate with survival. In multivariable analysis, older age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02-1.12; P =.009), CFF score less than 39 Hz (HR, 4.36; 95% CI, 1.67-11.37; P =.003), and MELD score (HR, 1.40; 95% CI, 1.21-1.63; P =.0001) were associated independently with survival during the follow-up period. In the validation cohort, CFF score less than 39 Hz and MELD score also were associated with patient survival during the follow-up period. MHE had no effect on the survival of patients with MELD scores less than 10 (among patients with CFF scores ≥39 Hz, 94.5% survived for 5 years vs 91.9% of patients with CFF scores <39 Hz; log-rank score, 0.64; P =.423). Fewer patients with MELD scores of 10-15 and MHE survived for 5 years (44.4%; 12 of 27) than those with MELD scores greater than 15 without MHE (61.5%; 8 of 13) (P <.05). Only 2 of 12 patients (16.7%) with MELD scores of 15 or higher and MHE survived for 5 years (log-rank score, 90.56; P =.0001). Conclusions MHE is associated with a reduced 5-year survival rate of patients with cirrhosis. Evaluation of MHE could help predict survival times and outcomes of patients with specific MELD scores. The CFF could help physicians determine prognoses of patients with cirrhosis. © 2015 AGA Institute. Source

Garcia-de-la-Asuncion J.,Hospital Clinico Universitario Of Valencia | Garcia-de-la-Asuncion J.,Institute Investigacion Sanitaria INCLIVA | Pastor E.,Hospital Clinico Universitario Of Valencia | Pastor E.,Institute Investigacion Sanitaria INCLIVA | And 8 more authors.
Redox Report | Year: 2013

Background: Cardiopulmonary bypass (CPB) in on-pump cardiac surgery can have harmful systemic effects, triggered in part by radical oxygen species (ROS) produced by ischemia-reperfusion in the heart and the lung. We determined the relationship between levels of oxidative stress markers (8-isoprostane and nitrites/nitrates) in plasma with aortic cross clamp duration in patients undergoing cardiac surgery with CPB. Methods: Thirty patients with CPB were studied: 14 with coronary artery bypass graft surgery and 16 with valve surgery. Plasma levels of 8-isoprostane, and nitrites/nitrates were measured over a 24-hour time course: before (T0) and after CPB: 5 minutes (T1), 1 hour (T2), 12 hours (T3), and 24 hours (T4). Results: Plasma levels of 8-isoprostane and nitrites/nitrates increased early after CPB, with a subsequent and progressive decline. Levels of oxidative stress markers in T1-T2 were positively correlated with the aortic cross clamp duration. Aortic cross clamp duration times greater than 50 minutes were correlated with higher oxidative stress levels. There were no significant differences in the levels of oxidative stress markers between surgery types. Conclusion: Cardiac surgery with CPB is associated with an early increase of oxidative stress markers in systemic blood. Aortic cross clamp duration is positively correlated with oxidative stress injury. © W. S. Maney & Son Ltd 2013. Source

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