15 research outputs found
Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease
With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)‒TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, and human microsomal stability and lack of neurotoxicity, and rescued memory, synaptic plasticity and neuroinflammation in an AD mouse model, after low dose chronic oral administration
Risk factors for non-diabetic renal disease in diabetic patients
Background. Diabetic patients with kidney disease have a high prevalence of non-diabetic renal disease (NDRD). Renal and
patient survival regarding the diagnosis of diabetic nephropathy (DN) or NDRD have not been widely studied. The aim of
our study is to evaluate the prevalence of NDRD in patients with diabetes and to determine the capacity of clinical and
analytical data in the prediction of NDRD. In addition, we will study renal and patient prognosis according to the renal
biopsy findings in patients with diabetes.
Methods. Retrospective multicentre observational study of renal biopsies performed in patients with diabetes from 2002 to
2014.
Results. In total, 832 patients were included: 621 men (74.6%), mean age of 61.7 6 12.8 years, creatinine was 2.8 6 2.2 mg/dL
and proteinuria 2.7 (interquartile range: 1.2–5.4) g/24 h. About 39.5% (n ¼ 329) of patients had DN, 49.6% (n ¼ 413) NDRD and
10.8% (n ¼ 90) mixed forms. The most frequent NDRD was nephroangiosclerosis (NAS) (n ¼ 87, 9.3%). In the multivariate
logistic regression analysis, older age [odds ratio (OR) ¼ 1.03, 95% CI: 1.02–1.05, P < 0.001], microhaematuria (OR ¼ 1.51, 95%
CI: 1.03–2.21, P ¼ 0.033) and absence of diabetic retinopathy (DR) (OR ¼ 0.28, 95% CI: 0.19–0.42, P < 0.001) were independently
associated with NDRD. Kaplan–Meier analysis showed that patients with DN or mixed forms presented worse renal
prognosis than NDRD (P < 0.001) and higher mortality (P ¼ 0.029). In multivariate Cox analyses, older age (P < 0.001), higher
serum creatinine (P < 0.001), higher proteinuria (P < 0.001), DR (P ¼ 0.007) and DN (P < 0.001) were independent risk factors for
renal replacement therapy. In addition, older age (P < 0.001), peripheral vascular disease (P ¼ 0.002), higher creatinine
(P ¼ 0.01) and DN (P ¼ 0.015) were independent risk factors for mortality.
Conclusions. The most frequent cause of NDRD is NAS. Elderly patients with microhaematuria and the absence of DR are
the ones at risk for NDRD. Patients with DN presented worse renal prognosis and higher mortality than those with NDRD.
These results suggest that in some patients with diabetes, kidney biopsy may be useful for an accurate renal diagnosis and
subsequently treatment and prognosis
Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs
Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold
Aproximación socio-antropológica a la obesidad infantil: estudio de caso en dos colegios de Valencia (España)
Smoking cessation opportunities in severe mental illness (tobacco intensive motivational and estimate risk — TIMER—): study protocol for a randomized controlled trial
There is an increased risk of premature death in people with severe mental illness (SMI). Respiratory
disorders and cardiovascular disease are leading causes of increased mortality rates in these patients, and tobacco
consumption remains the most preventable risk factor involved. Developing new tools to motivate patients
towards cessation of smoking is a high priority. Information on the motivational value of giving the lung age and
prevention opportunities is unknown in this high-risk population. In the context of community care, screening and early detection of lung damage could potentially
be used, together with mobile technology, in order to produce a prevention message, which may provide
patients with SMI with a better chance of quitting smoking.This study receives funding by the Spanish Ministry of Economy, Industry
and Competitiveness, Instituto Carlos III (FIS PI16/00802)
Diagénesis temprana de metales pesados en sedimentos del Pacífico adyacente a Ia boca del Golfo de California, Mexico
Con objeto de estudiar la partici6n geoquímica de los metales pesados, se utilizaron dos núcleos de sedimentos, procedentes de dos sitios adyacentes a la boca del Golfo de California en el Pacífico mexicano. Fueron separadas cinco fracciones operacionalmente definidas y las concentraciones de Cd, Cu, Co, Cr, Fe, Mn, Ni, Pb y Zn se determinaron en cada una de las muestras por técnicas de absorci6n atómica. Los resultados indican una conducta contrastante de las fases y los elementos asociadas durante la diagénesis temprana. Los datos de la fracción carbonatada, en el núcleo colectado en la depresión de la cuenca Mazatlán, permiten sugerir la formación de siderita (FeC03) con la profundidad de la columna sedimentaria, con la presencia del Pb como accesorio. Se propone un modelo simple para explicar la transferencia de las formas del Mn y Fe oxidable y reducible ala litogénica (silicoalurninatos); siendo esta transformaci6n de manera gradual y conforme se sepulta el material sedimentario, demostrándose un cambio concordante de tipo exponencial en las proporciones de los metales en las tres fases
Starch Debranching Enzyme Activity and Its Effects on Some Starch Physicochemical Characteristics in Developing Substituted and Complete Triticales (X Triticosecale
La prevalencia de sarcopenia en residencias de España: comparación de los resultados del estudio multicéntrico ELLI con otras poblaciones
Risk factors for non-diabetic renal disease in diabetic patients
Background. Diabetic patients with kidney disease have a high prevalence of non-diabetic renal disease (NDRD). Renal and
patient survival regarding the diagnosis of diabetic nephropathy (DN) or NDRD have not been widely studied. The aim of
our study is to evaluate the prevalence of NDRD in patients with diabetes and to determine the capacity of clinical and
analytical data in the prediction of NDRD. In addition, we will study renal and patient prognosis according to the renal
biopsy findings in patients with diabetes.
Methods. Retrospective multicentre observational study of renal biopsies performed in patients with diabetes from 2002 to
2014.
Results. In total, 832 patients were included: 621 men (74.6%), mean age of 61.7 6 12.8 years, creatinine was 2.8 6 2.2 mg/dL
and proteinuria 2.7 (interquartile range: 1.2–5.4) g/24 h. About 39.5% (n ¼ 329) of patients had DN, 49.6% (n ¼ 413) NDRD and
10.8% (n ¼ 90) mixed forms. The most frequent NDRD was nephroangiosclerosis (NAS) (n ¼ 87, 9.3%). In the multivariate
logistic regression analysis, older age [odds ratio (OR) ¼ 1.03, 95% CI: 1.02–1.05, P < 0.001], microhaematuria (OR ¼ 1.51, 95%
CI: 1.03–2.21, P ¼ 0.033) and absence of diabetic retinopathy (DR) (OR ¼ 0.28, 95% CI: 0.19–0.42, P < 0.001) were independently
associated with NDRD. Kaplan–Meier analysis showed that patients with DN or mixed forms presented worse renal
prognosis than NDRD (P < 0.001) and higher mortality (P ¼ 0.029). In multivariate Cox analyses, older age (P < 0.001), higher
serum creatinine (P < 0.001), higher proteinuria (P < 0.001), DR (P ¼ 0.007) and DN (P < 0.001) were independent risk factors for
renal replacement therapy. In addition, older age (P < 0.001), peripheral vascular disease (P ¼ 0.002), higher creatinine
(P ¼ 0.01) and DN (P ¼ 0.015) were independent risk factors for mortality.
Conclusions. The most frequent cause of NDRD is NAS. Elderly patients with microhaematuria and the absence of DR are
the ones at risk for NDRD. Patients with DN presented worse renal prognosis and higher mortality than those with NDRD.
These results suggest that in some patients with diabetes, kidney biopsy may be useful for an accurate renal diagnosis and
subsequently treatment and prognosis