Efectos de la josamicina en aurículas aisladas de rata y músculos papilares de cobayo

Depto. de Farmacología y ToxicologíaFac. de MedicinaTRUEProQuestpu

Emerging therapeutic strategies to enhance HDL function

Epidemiologic studies indicate a strong inverse correlation between plasma levels of high-density lipoproteins (HDL) and cardiovascular disease (CVD). The most relevant cardioprotective mechanism mediated by HDL is thought to be reverse cholesterol transport (RCT). New insights in HDL biology and RCT have allowed the development of promising agents aimed to increase HDL function and promote atherosclerosis regression. In this regard, apo-AI analogs and CETP inhibitors dalcetrapib and anacetrapib have aroused a great interest and opened new expectations in the treatment of CVD

Teoría de nudos y aplicaciones

El presente trabajo consiste en una breve introducción a la teoría de nudos, con especial hincapié en la teoría de nudos virtuales (una joven rama de este campo con prometedoras perspectivas de futuro que estudia una generalización del concepto de nudo clásico) y su conexión (siendo ésta de carácter topológico) con unos elementos de naturaleza algebraica. La memoria está dividida en tres partes fundamentales: preliminares (apéndice A), códigos de Gauss (capítulo 1) y planaridad (capítulo 2). La lectura debe comenzar con el apéndice A: en éste se expone lo necesario para entender el desarrollo de los capítulos 1 y 2. Se introducen conceptos básicos de teoría de nudos y teoría de nudos virtuales y, debido a la fuerte analogía entre nudos y grafos, también de teoría de grafos. Esta parte presenta una visión general para posicionarse en el contexto de lo estudiado, proporcionando las herramientas para afrontar cuestiones más particulares. En el capítulo 1 entraremos en algo más concreto: la capacidad de unas secuencias de números, letras y signos para representar los nudos virtuales, los llamados códigos de Gauss. Desarrollaremos de forma natural y detallada el proceso para demostrar que estos códigos verdaderamente sirven para representar nudos virtuales y nos familiarizaremos mejor con el entorno sobre el que estamos trabajando. El último y segundo capítulo servirá para demostrar la utilidad de este nuevo enfoque para estudiar los nudos virtuales: el hecho de trabajar con códigos de Gauss nos permitirá obtener nuevos resultados y además, ser capaces de desarrollar algoritmos para el estudio de nudos virtuales. En definitiva, se trata de una breve inmersión en una línea de investigación actual, la teoría de nudos virtuales, mostrando su motivación y (parte de) la utilidad de la misma

Vascular Dysfunction in a Transgenic Model of Alzheimer's Disease: Effects of CB1R and CB2R Cannabinoid Agonists

There is evidence of altered vascular function, including cerebrovascular, in Alzheimer's disease (AD) and transgenic models of the disease. Indeed vasoconstrictor responses are increased, while vasodilation is reduced in both conditions. β-Amyloid (Aβ) appears to be responsible, at least in part, of alterations in vascular function. Cannabinoids, neuroprotective and anti-inflammatory agents, induce vasodilation both in vivo and in vitro. We have demonstrated a beneficial effect of cannabinoids in models of AD by preventing glial activation. In this work we have studied the effects of these compounds on vessel density in amyloid precursor protein (APP) transgenic mice, line 2576, and on altered vascular responses in aortae isolated ring. First we showed increased collagen IV positive vessels in AD brain compared to control subjects, with a similar increase in TgAPP mice, which was normalized by prolonged oral treatment with the CB1/CB2 mixed agonist WIN 55,212-2 (WIN) and the CB2 selective agonist JWH-133 (JWH). In Tg APP mice the vasoconstriction induced by phenylephrine and the thromboxane agonist U46619 was significantly increased, and no change in the vasodilation to acetylcholine (ACh) was observed. Tg APP displayed decreased vasodilation to both cannabinoid agonists, which were able to prevent decreased ACh relaxation in the presence of Aβ. In summary, we have confirmed and extended the existence of altered vascular responses in Tg APP mice. Moreover, our results suggest that treatment with cannabinoids may ameliorate the vascular responses in AD-type pathology.This work was supported by the Council of Madrid (S- BIO/0170/2006 and P2010/BMD-2349 to MLC) and by Instituto de Salud Carlos III/FISS (PI12/00590 to TT). AM received a fellowship from the Spanish Ministry of Education and Science and JN-D from FISS. Dr. R. Martínez-Murillo is acknowledged for preliminary EM experiments.Peer reviewedPeer Reviewe

Role of TGF-β1 and MAP Kinases in the Antiproliferative Effect of Aspirin in Human Vascular Smooth Muscle Cells

We aimed to test the antiproliferative effect of acetylsalicylic acid (ASA) on vascular smooth muscle cells (VSMC) from bypass surgery patients and the role of transforming growth factor beta 1 (TGF-beta1).VSMC were isolated from remaining internal mammary artery from patients who underwent bypass surgery. Cell proliferation and DNA fragmentation were assessed by ELISA. Protein expression was assessed by Western blot. ASA inhibited BrdU incorporation at 2 mM. Anti-TGF-beta1 was able to reverse this effect. ASA (2 mM) induced TGF-beta1 secretion; however it was unable to induce Smad activation. ASA increased p38(MAPK) phosphorylation in a TGF-beta1-independent manner. Anti-CD105 (endoglin) was unable to reverse the antiproliferative effect of ASA. Pre-surgical serum levels of TGF-beta1 in patients who took at antiplatelet doses ASA were assessed by ELISA and remained unchanged.In vitro antiproliferative effects of aspirin (at antiinflammatory concentration) on human VSMC obtained from bypass patients are mediated by TGF-beta1 and p38(MAPK). Pre-surgical serum levels of TGF- beta1 from bypass patients who took aspirin at antiplatelet doses did not change

Mx1, OAS1 and OAS2 polymorphisms are associated with the severity of liver disease in HIV/HCV-coinfected patients: A cross-sectional study

The mechanisms involved in the chronic hepatitis C progression are incompletely understood. The aim was to analyze the association between 2'5'oligoadenylate synthetase 1,2 and 3 (OAS1-3) and myxovirus resistance proteins 1 (Mx1) polymorphisms and severity of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. We performed a cross-sectional study in 219 patients that underwent a liver biopsy. DNA genotyping for Mx1 (rs469390), OAS1 (rs2285934), OAS2 (rs1293762) and OAS3 (rs2010604) was performed by using GoldenGate assay. The outcome variables ion liver biopsy were: (i) significant fibrosis (F ≥ 2); (ii) moderate activity grade (A ≥ 2). Additive model of inheritance for genetic association test was used. The likelihood of having significant fibrosis (F ≥ 2) was lower in patients carrying OAS2 rs1293762 A allele [adjusted odds ratio (aOR) = 0.51; p = 0.040]. Besides, the likelihood of having moderate activity grade (A ≥ 2) was higher in patients carrying Mx1 rs464397 C allele (aOR = 1.63; p = 0.028) and Mx1 rs469390 G allele (aOR = 1.97; p = 0.005), while it was lower in patients carrying OAS1 rs2285934 A allele (aOR = 0.64; p = 0.039) and OAS2 rs1293762 A allele (aOR = 0.41; p = 0.009). In conclusion, Mx1 and OAS1-2 polymorphisms were associated with the severity of liver disease in HIV/HCV-coinfected patients, suggesting a significant role in the progression of hepatic fibrosis.This work has been supported by grants given by Fondo de Investigación de Sanidad en España (FIS) [Spanish Health Founds for Research] [grant numbers PI14/01094, PI14CIII/00011] and Red Española de Investigación en SIDA (RIS) [AIDS Research Network] [grant numbers RD16CIII/0002/0002RD16 and RD16/0025/0017]. This work has been (partially) funded by the RD12/0017 project as part of the Plan Nacional R + D + I and cofinanced by ISCIII- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). J.B. is an investigator from the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS). M.G.A., D.P.T. and M.A.J.S. are supported by “Instituto de Salud Carlos III” [grant numbers CD12/00442, CM12/00043, CD13/00013, respectively]. The authors thank the Spanish National Genotyping Center (CeGen) for providing SNP genotyping services (http://www.cegen.org).S

Impact of patatin-like phospholipase domain-containing 3 gene polymorphism (rs738409) on severity of liver disease in HIV/hepatitis C virus-coinfected patients

Objective: To analyze the association between patatin-like phospholipase domain-containing 3 gene (PNPLA3) rs738409 polymorphism and severity of liver disease in HIV/hepatitis C virus-coinfected patients. Methods: We performed a cross-sectional study of 215 patients who underwent a liver biopsy. PNPLA3 rs738409 polymorphism was genotyped using GoldenGate assay. The outcome variables were as follows: advanced fibrosis (F ≥3 and FIB-4 ≥3.25), rapid fibrosis progression (FPR ≥0.10 fibrosis units/year), severe activity grade (A≥3), and steatosis (fatty hepatocytes ≥10%). The genetic association analysis was carried out according to an additive genetic model through logistic regressions adjusted by the most significant covariables. Results: Overall, 21.4% had F at least 3, 8.9% had FIB-4 at least 3.25, 11.4% had A at least 3, 60.6% had steatosis, and 32.5% had FPR at least 0.10. For each rs738409 G allele, we found an increased frequency of patients with advanced fibrosis (F at least 3) (0% CC, 18.5% CG, and 25.2% GG; P = 0.049) and FIB-4 at least 3.25 (0% CC, 3.8% CG, and 13.2% GG; P = 0.016). Furthermore, for each rs738409 G allele, the odds of having F at least 3 increased 2.15 times (95% confidence interval=1.07; 4.35; P = 0.029) and having FIB-4 at least 3.25 increased 8.77 times (95% of confidence interval = 1.11; 69.0; P = 0.039). Note that rs738409 G allele carriers tended to higher likelihood of having FPR at least 0.10, but statistical significance was not reached (P = 0.054). Finally, we did not find any association for A at least 3 and liver steatosis. Conclusion: PNPLA3 rs738409 polymorphism was associated with the severity of liver fibrosis in patients coinfected with HIV and hepatitis C virus, suggesting that this polymorphism might also play a significant role in the progression of hepatic fibrosis in this group of patients.This work has been supported by grants given by Fondo de Investigación de Sanidad en España (FIS) (Spanish Health Founds for Research) (grant numbers PI11/01556, PI14/01094, PI11/00245, PI14CIII/00011), and ‘Fundación para la Investigación y la Prevención del Sida en España’ (FIPSE) (grant number 361020/10). This work has been (partially) funded by the RD12/0017/0024 and RD12/0017/0004 projects as part of the Plan Nacional R+D+I and cofinanced by ISCIII – Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). ‘Instituto de Salud Carlos III’ (grant numbers CD12/00442, CD13/00013 and RD12/0017/0024, respectively). This work has been (partially) funded by the RD12/0017 project as part of the Plan Nacional R+D+I and cofinanced by ISCIII – Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER).S

Age-dependent defective TGF-beta1 signaling in patients undergoing coronary artery bypass grafting

Background: Transforming growth factor beta (TGF-beta 1) is a pleiotropic cytokine, which is deregulated in atherosclerosis; however the role of age in this process is unknown. We aimed to assess whether TGF-beta 1 signaling is affected by age. Methods: Vascular smooth muscle cells (VSMC) were obtained from patients undergoing abdominal surgery. Levels of TGF-beta 1 were measured by ELISA in sera from 169 patients undergoing coronary artery bypass grafting (CABG). The p27 expression was determined by Western blot from internal mammary arteries (IMA) obtained from CABG patients (n = 13). In VSMC from these patients undergoing abdominal surgery, secretion of TGF-beta 1 was determined by ELISA of cell-conditioned media. Results: In VSMC from aged patients we observed a lower TGF-beta 1 secretion, measured as TGF-beta 1 concentration in cell conditioned medium (p < 0.001). This effect was correlated to an age-dependent decrease of p27 expression in IMA from aged CABG patients. In a similar manner, there was an age-dependent decrease of serum TGF-beta 1 levels in CABG patients (p = 0.0195). Conclusions: VSMC from aged patients showed a higher degree of cellular senescence and it was associated to a lower TGF-beta 1 secretion and signaling.S

Decreased pre-surgical CD34+/CD144+ cell number in patients undergoing coronary artery bypass grafting compared to coronary artery disease-free valvular patients

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease has been linked to endothelial progenitor cell (EPC) depletion and functional impairment in atherosclerosis and aortic stenosis. EPCs may play a pivotal role in vascular grafting. However, the EPC depletion in coronary artery bypass grafting (CABG) patients has not been compared to coronary artery disease-free valvular replacement patients with aortic stenosis.</p> <p>Methods</p> <p>We aimed to assess the basal number of CD34⁺/KDR⁺and CD34⁺/CD144⁺cells in CABG patients, compared to aortic stenosis valvular replacement patients. 100 patients (51 CABG and 49 valvular surgery ones) were included in the present study. All CABG or valvular patients had angiographic demonstration of the presence or the absence of coronary artery disease, respectively. Numbers of CD34⁺/KDR⁺and CD34⁺/CD144⁺were assessed by flow cytometry of pre-surgical blood samples.</p> <p>Results</p> <p>We found a lower number of CD34⁺/CD144⁺cells in CABG patients compared to valvular patients (0.21 ± 0.03% vs. 0.47 ± 0.08%), and this difference remained statistically significant after the <it>P </it>was adjusted for multiple comparisons (<it>P </it>= 0.01428). Both groups had more EPCs than healthy controls.</p> <p>Conclusions</p> <p>Pre-surgical CD34⁺/CD144⁺numbers are decreased in CABG patients, compared to valvular patients with absence of coronary disease.</p