Actividad del Sistema Renina-Angiotensina en relación con sus polimorfismos genéticos

La realización del presente estudio sobre sujetos jóvenes y sanos no hipertensos tiene dos objetivos primordiales: El primero es analizar la relación de los polimorfismos de los genes del Sistema Renina-Angiotensina, el M235T del gen del angiotensinógeno, el Inserción/Delección del gen de la ECA y el A1166C del gen del receptor AT1 para la angiotensina II, con los niveles en plasma de angiotensina I, angiotensina II y angiotensina-(1-7), todas sustancias peptídicas activas del sistema El segundo es relacionar dichos polimorfismos mediante las distintas razones de conversión y correlaciones, de angiotensina I a angiotensina II, de angiotensina I a angiotensina-(1-7), y de angiotensina II a angiotensina-(1-7), con variaciones en la regulación del eje renina-angiotensina. Tras la consecución dicho estudio, no se encontraron diferencias significativas en los niveles de los péptidos de la angiotensina analizados en la población distribuida por genotipos. Los niveles de angiotensina-(1-7), al igual que las razones de conversión A-(1-7)/AI y A-(1-7)/AII, fueron significativamente mayores en varones que en mujeres en sangre circulante. Los polimorfismos influyeron de forma distinta en los valores medios de los péptidos de la angiotensina en hombres y en mujeres, produciendo equilibrios diferentes. Por este motivo deberían ser siempre analizados en relación al sexo

Expression of epicardial adipose tissue thermogenic genes in patients with reduced and preserved ejection fraction heart failure

[Abstract] Epicardial adipose tissue has been proposed to participate in the pathogenesis of heart failure. The aim of our study was to assess the expression of thermogenic genes (Uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and PR-domain-missing 16 (PRDM16) in epicardial adipose tissue in patients with heart failure, stablishing the difference according to left ventricular ejection fraction (reduced or preserved). Among the 75 patients in our study, 42.7% (n=32) had reduced left ventricular ejection fraction. UCP1, PGC1α and PRDM16 mRNA in EAT were significantly lower in patients with reduced left ventricular ejection fraction. Multiple regression analysis showed that age, male gender, body max index, presence of obesity, type-2-diabetes mellitus, hypertension and coronary artery disease and left ventricular ejection fraction were associated with the expression levels of UCP1, PGC1α and PRDM16 mRNA. Thermogenic genes expressions in epicardial adipose tissue (UCP1: OR 0.617, 95%CI 0.103-0.989, p=0.042; PGC1α: OR 0.416, 95%CI 0.171-0.912, p=0.031; PRDM16: OR 0.643, 95%CI 0.116-0.997, p=0.044) were showed as protective factors against the presence of heart failure with reduced left ventricular ejection fraction, and age (OR 1.643, 95%CI 1.001-3.143, p=0.026), presence of coronary artery disease (OR 6.743, 95%CI 1.932-15.301, p<0.001) and type-2-diabetes mellitus (OR 4.031, 95%CI 1.099-7.231, p<0.001) were associated as risk factors. The adequate expression of thermogenic genes has been shown as possible protective factors against heart failure with reduced ejection fraction, suggesting that a loss of functional epicardial adipose tissue brown-like features would participate in a deleterious manner on heart metabolism. Thermogenic genes could represent a future novel therapeutic target in heart failure.Ministerio de Salud, Servicios Sociales e Igualdad; PI13/02542Ministerio de Salud, Servicios Sociales e Igualdad; PI11/01661Red de Investigación Cardiovascular (España), RD12/0042/003

ERK5/BMK1 is a novel target of the tumor suppressor VHL: implication in clear cell renal carcinoma

Hi ha quatre pàgines de material suplementari sense numeracióExtracellular signal-regulated kinase 5 (ERK5), also known as big mitogen-activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Uptake and depuration of three common antibiotics in benthic organisms: sea cucumber (Holothuria tubulosa), snakelocks anemone (Anemonia sulcata) and beadlet anemone (Actinia equina)

Antibiotics are widely used drugs in human and veterinary medicine, which has attracted great attention in relation to the development of bacterial resistance, currently a problem of great concern for governments and states, as it is related to the resurgence of infectious diseases already eradicated. Understanding the bioaccumulation of antibiotics in aquatic organisms is an important key to understanding their risk assessment. The present study was designed to study the bioaccumulation of target antibiotics in relevant organisms inhabiting benthic marine environments. The uptake and elimination of ciprofloxacin (CIP), sulfamethoxazole (SMX) and trimethoprim (TMP) were investigated in sea cucumbers (Holothuria tubulosa), snakelock anemone (Anemonia sulcata) and beadlet anemone (Actinia equina) under controlled laboratory conditions. The results show that antibiotics have a particular trend over time during all periods of absorption and depuration. The tissue distribution of antibiotics in sea cucumber is strongly influenced by the structure of the compounds, while CIP is concentrated in the body wall; TMP is concentrated in the digestive tract. Two different approaches were used to estimate bioconcentration factors (BCFs) in different animal models, based on toxicokinetic data and measured steady-state concentrations. The BCF ranges were 456–2731 L/kg, 6–511 L/kg and 9–100 L/kg for TMP, CIP and SMX, respectively. The estimated BCF values obtained classify TMP as cumulative in A. equina and H. tubulosa, underlining the potential bioconcentration in these marine organisms. A correlation was observed between the BCFs of the target antibiotics and the octanol-water distribution coefficient (Dow) (r² > 0.7). The animal-specific BCF followed the order of beadlet anemone > sea cucumber > snakelock anemone

Accumulation and Metabolization of the Antidepressant Venlafaxine and its Main Metabolite o-desmethylvenlafaxine in non-target Marine Organisms Holothuria Tubulosa, Anemonia Sulcata and Actinia Equina

The assessment of exposure to the antidepressant venlafaxine and its major metabolite o-desmethylvenlafaxine in Holothuria tubulosa, Anemonia sulcata and Actinia equina is proposed. A 28-day exposure experiment (10 μg/L day) followed by a 52-day depuration period was conducted. The accumulation shows a first-order kinetic process reaching an average concentration of 49,125/54342 ng/g dw in H. tubulosa and 64,810/93007 ng/g dw in A. sulcata. Venlafaxine is considered cumulative (BCF > 2000 L/kg dw) in H. tubulosa, A. sulcata and A. equina respectively; and o–desmethylvenlafaxine in A. sulcata. Organism-specific BCF generally followed the order A. sulcata > A. equina > H. tubulosa. The study revealed differences between tissues in metabolizing abilities in H. tubulosa this effect increases significantly with time in the digestive tract while it was negligible in the body wall. The results provide a description of venlafaxine and o-desmethylvenlafaxine accumulation in common and non-target organisms in the marine environment.Ministerio de Ciencia e Innovación PID2020-117641RB-I0Junta de Andalucía B.RNM.362.UGR20, P20_0055

Bioconcentration of pharmaceuticals in benthic marine organisms (Holothuria tubulosa, Anemonia sulcata and Actinia equina) exposed to environmental contamination by atenolol and carbamazepine

The present work assess the bioconcentration kinetics of atenolol (ATN) and carbamazepine (CBZ) in common marine organisms including Holothuria tubulosa, Anemonia sulcata and Actinia equina under controlled laboratory conditions. CBZ exhibited higher uptake and excretion rates resulting higher bioconcentration factor (BCF) (41–537 L/kg for CBZ vs 7–50 L/kg for ATN) although both are below the limits established by the European Union (EU). The measured BCF using kinetic data showed some differences with those predicted using the concentrations measured at the steady-state, probably explained because the steady state was not ready reached. The animal-specific BCF followed the order of Holothuria tubulosa > Actinia equina > Anemonia sulcata for ATN while was the opposite for CBZ. The study highlighted between-tissues differences in the digestive tract and the body wall of the Holothuria tubulosa. The work presented is the first to model bioconcentration of ATN and CBZ in holothurian and anemone animal models

Overexpression of scavenger receptor and infiltration of macrophage in epicardial adipose tissue of patients with ischemic heart disease and diabetes

Abstract Background Oxidized low-density lipoproteins and scavenger receptors (SRs) play an important role in the formation and development of atherosclerotic plaques. However, little is known about their presence in epicardial adipose tissue (EAT). The objective of the study was to evaluate the mRNA expression of different SRs in EAT of patients with ischemic heart disease (IHD), stratifying by diabetes status and its association with clinical and biochemical variables. Methods We analyzed the mRNA expression of SRs (LOX-1, MSR1, CXCL16, CD36 and CL-P1) and macrophage markers (CD68, CD11c and CD206) in EAT from 45 patients with IHD (23 with type 2 diabetes mellitus (T2DM) and 22 without T2DM) and 23 controls without IHD or T2DM. Results LOX-1, CL-P1, CD68 and CD11c mRNA expression were significantly higher in diabetic patients with IHD when compared with those without T2DM and control patients. MSR1, CXCL16, CD36 and CD206 showed no significant differences. In IHD patients, LOX-1 (OR 2.9; 95% CI 1.6–6.7; P = 0.019) and CD68 mRNA expression (OR 1.7; 95% CI 0.98–4.5; P = 0.049) were identified as independent risk factors associated with T2DM. Glucose and glycated hemoglobin were also shown to be risk factors. Conclusions SRs mRNA expression is found in EAT. LOX-1 and CD68 and were higher in IHD patients with T2DM and were identified as a cardiovascular risk factor of T2DM. This study suggests the importance of EAT in coronary atherosclerosis among patients with T2DM