Supramolecular Assembly of Benzimidazole Derivatives and Applications

Herein, we focus on the chemical and physical properties of benzimidazole and its derivatives used for the synthesis of supramolecular materials. The design and modification of benzimidazole opens the scope of the diversity of structures (different sizes and morphologies) that can be built. The synthesized materials include not only small coordination complexes but also isolated crystals, metal-organic frameworks, metal-coordination polymers, smart nanocontainers, and more advanced macrostructures such as microflowers and nanowires. These supramolecular structures are based on noncovalent interactions, mostly on metal coordination chemistry and π-π stacking interactions. Moreover, the same molecule, due to its chemical structure, can undergo both sorts of interactions in order to induce the self-assembly into supramolecular materials. In this process, as it is shown in this chapter, the conditions used for the assembly determine the final structure and morphology of the fabricated macromolecule. Finally, we show most recent applications of these materials in the field of sensing, photoluminescence, fuel cell, and fabrication of new nanostructures

El índice neutrófilo/linfocito como marcador de disfunción sistémica endotelial en sujetos asintomáticos

ResumenFundamento y objetivoEl índice neutrófilo/linfocito es un marcador inflamatorio de valor pronóstico en enfermedades cardiovasculares. El objetivo del presente trabajo es valorar la asociación entre el índice neutrófilo/linfocito y la alteración del cociente albúmina/creatinina urinario como marcador precoz de disfunción endotelial sistémica asociada a enfermedad microvascular y riesgo cardiovascular, en sujetos asintomáticos.Materiales y métodosSe realizó un estudio transversal en 1.816 sujetos asintomáticos. Se excluyó del a estudio aquellos pacientes que presentaron antecedentes de enfermedad cardiovascular, los que recibían tratamiento con fármacos antiproteinúricos (inhibidores de la enzima conversora de angiotensina y antagonistas de los receptores de la angiotensina II) y aquellos que presentaron un cociente albúmina/creatinina superior a 300mg/dL. La variable desenlace del estudio fue la alteración del cociente albúmina/creatinina urinario.ResultadosEl índice neutrófilo/linfocito resultó significativamente asociado a la alteración del cociente albúmina/creatinina urinario, tanto en el estudio univariante como en el multivariante, independientemente de otros cofactores como la edad, la hipertensión arterial, la diabetes, la dislipidemia o el filtrado glomerular patológico. El análisis de la sensibilidad y la especificidad de distintos niveles del índice neutrófilo/linfocito permitió generar 3 grupos de riesgo de alteración del cociente albúmina/creatina urinario: riesgo bajo con un cociente neutrófilo/linfocito < 1,5, riesgo intermedio con cociente neutrófilo/linfocito entre 1,5 y 3 y riesgo alto con un cociente neutrófilo/linfocito > 3. La proporción relativa de alteración del cociente albúmina/creatinina urinario, en los 3 grupos de riesgo, aumentaba en razón del valor del índice neutrófilo/linfocito de forma independiente al resto de cofactores.ConclusionesEl índice neutrófilo/linfocito surge como un potencial marcador de disfunción endotelial sistémica económico, rápido, no invasivo e independiente de otros factores conocidos, en sujetos asintomáticos.AbstractBackground and objectiveThe neutrophil-to-lymphocyte ratio has demonstrated to be a prognostic inflammatory marker in cardiovascular disease. The objective of this study is to evaluate the association between neutrophil-to-lymphocyte ratio and pathologic urinary albumin/creatinine ratio as an early marker of cardiovascular risk and systemic endothelial dysfunction, associated with microvascular disease, in asymptomatic subjects.Materials and methodsA unicenter cross-sectional study was conducted, including 1816 asymptomatic subjects. Patients with previous cardiovascular disease, those who were treated with ACE inhibitors and/or angiotensin II receptor blockers and patients with albumin/creatinine ratio over 300mg/g were excluded. The outcome of the study was the presence of a pathologic urinary albumin/creatinine ratio.ResultsThe neutrophil-to-lymphocyte ratio was significantly associated with altered urinary albumin/creatinine ratio in the univariate analysis and after adjustment for other known endothelial and cardiovascular risk factors (age, hypertension, dyslipidaemia, diabetes or altered glomerular filtration rate). Based on the sensitivity and specificity of different neutrophil-to-lymphocyte ratio thresholds, 3 risk groups were created for altered urinary albumin/creatinine ratio: low risk in those with neutrophil-to-lymphocyte ratio < 1.5, intermediate risk in patients between 1.5 and 3, and high risk in those with neutrophil-to-lymphocyte ratio > 3. These groups were found to have a statistically significant and independent prognostic power for altered urinary albumin/creatinine ratio in asymptomatic patients.ConclusionsThe neutrophil-to-lymphocyte ratio appears to be a cost-efficient, non-invasive and independent potential marker of systemic endothelial dysfunction in asymptomatic subjects

Metal-Organic Enzyme Nanogels as Nanointegrated Self-Reporting Chemobiosensors

[EN] A fluorometric glucose biosensor based on fine-tuned chemoenzymatic nanohybrids is herein proposed. The successful integration of an engineered glucose oxidase enzyme and an optically responsive polymeric nanogel in a single entity has led to the fabrication of a highly efficient glucose chemobiosensor. The optical responsiveness has been achieved by the loading of preactivated polymeric hydrogel with fluorescent lanthanide, i.e., cerium (III), cations. A comprehensive investigation of the responsiveness of the biomaterial revealed the interplay between the oxidation state of the cerium lanthanide and the fluorescence emission of the polymer. Finally, a full structural, chemical, and biochemical characterization of the reported system supports the chemobiosensors as robust, specific, and sensitive materials that could be utilized to faithfully quantify the amount of glucose in tear fluids.The authors gratefully acknowledge the financial support from the Spanish Research Agency (AEI) for the financial support (PID2019-110239RB-I00 from I+D call and RYC2018-025923-I from RyC program), including FEDER funds, IKERBASQUE-Basque Foundation for Science, and BBVA foundation (Leonardo Fellowships, IN[21] _CBB_QUI_0086). Open Access funding is provided by University of Basque Country

Tunable Polymeric Scaffolds for Enzyme Immobilization

The number of methodologies for the immobilization of enzymes using polymeric supports is continuously growing due to the developments in the fields of biotechnology, polymer chemistry, and nanotechnology in the last years. Despite being excellent catalysts, enzymes are very sensitive molecules and can undergo denaturation beyond their natural environment. For overcoming this issue, polymer chemistry offers a wealth of opportunities for the successful combination of enzymes with versatile natural or synthetic polymers. The fabrication of functional, stable, and robust biocatalytic hybrid materials (nanoparticles, capsules, hydrogels, or films) has been proven advantageous for several applications such as biomedicine, organic synthesis, biosensing, and bioremediation. In this review, supported with recent examples of enzyme-protein hybrids, we provide an overview of the methods used to combine both macromolecules, as well as the future directions and the main challenges that are currently being tackled in this field.This work is in the framework of a project that has received funding from the Spanish Ministry of Economy and Competitiveness (MINECO) and FEDER funds in the frame of "Plan Nacional -Retos para la Sociedad" call with the grant references MAT2017-88808-R and PID2019-110239RB-I00. This work was performed under the Maria de Maeztu Units of Excellence Programme -MDM-2016-0618. AB thanks the Spanish Research Agency (AEI) for the funds within Ramon y Cajal programme (RYC2018-025923-I). AR-A thanks the Basque Government for his Ph.D. fellowship (PRE_2019_2_0147)

A Versatile Chemoenzymatic Nanoreactor that Mimics NAD(P)H Oxidase for the In Situ Regeneration of Cofactors

Herein, we report a multifunctional chemoenzymatic nanoreactor (NanoNOx) for the glucose-controlled regeneration of natural and artificial nicotinamide cofactors. NanoNOx are built of glucose oxidase-polymer hybrids that assemble in the presence of an organometallic catalyst: hemin. The design of the hybrid is optimized to increase the effectiveness and the directional channeling at low substrate concentration. Importantly, NanoNOx can be reutilized without affecting the catalytic properties, can show high stability in the presence of organic solvents, and can effectively oxidize assorted natural and artificial enzyme cofactors. Finally, the hybrid was successfully coupled with NADH-dependent dehydrogenases in one-pot reactions, using a strategy based on the sequential injection of a fuel, namely, glucose. Hence, this study describes the first example of a hybrid chemoenzymatic nanomaterial able to efficiently mimic NOx enzymes in cooperative one-pot cascade reactions.The authors gratefully acknowledge the financial support from the Spanish Research Agency (AEI) for the financial support (PID2019-110239RB-I00 from I+D call and RYC2018-025923-I from RyC program), including FEDER funds; IKERBASQUE-Basque Foundation for Science, BBVA foundation (Leonardo Fellowships, IN[21]_CBB_QUI_0086) and Maria de Maeztu Units of Excellence Programme: Grant Number CEX2020-001038-M. AR-A thanks the Basque Government for his Ph.D. fellowship (PRE_2021_2_0151). Open Access funding is provided by the University of the Basque Country (UPV/EHU)

Recent advances and future perspectives on porous materials for biomedical applications

Unformatted postprint version of the accepted articleThe authors gratefully acknowledge financial support from MCIN/AEI/10.13039/501100011033 and FEDER (RTI2018-098951- B-I00, RTI2018-096294-B-C32), IKERBASQUE-Basque Foundation for Science, Basque Government (Elkartek projects KK- 2019/00086 and KK-2020/00010; proyectos de investigacio´ n ba´ sica/aplicada PIBA 2020 1 0056, IT1069-16), Gipuzkoa Provincial Council (2019-CIEN-000075-01). MSO and S.C-E acknowledge support by the Marie-Slodowska-Curie Action under the H2020 framework program, with the projects ‘THERMUCNA’ [896775] and ‘PRIUS-TE’ [845488], respectively. A.B. thanks to the Spanish Research Agency (AEI) for the financial support (PID2019-110239RB-I00 from I+D call and RYC2018-025923-I from RyC program), including FEDER funds; and BBVA foundation (Leonardo Fellowships, IN [21] CBB QUI 0086). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

Relación entre las fases precoces de la enfermedad renal y el síndrome metabólico

Advanced kidney disease is a major health problem due to its association with high cardiovascular morbidity and mortality. Early recognition of advanced kidney disease is the mainstay to avoid its progression. Since metabolic syndrome and insulin resistance are risk factors for both cardiovascular and advanced kidney disease, we investigated the relationship of early kidney disease (EKD) with metabolic syndrome and insulin resistance, and their association with surrogate markers of arteriosclerosis. METHODS: We studied 1498 subjects. Insulin resistance was defined as HOMA >/=3.7 mmol (muU)/L(2) and EKD as stages 1 and 2 of the NKF-KDOQI. Carotid intima-media thickness was used as a surrogate marker of arteriosclerosis. RESULTS: The presence of one trait of metabolic syndrome was associated with an odds ratio (OR) for EKD of 2.3 (95% confidence interval [CI], 1.18-4.48) that increased to 6.72 (95% CI, 3.56-13.69) in subjects with the syndrome. All the traits of the syndrome except low level of high-density lipoproteins showed an increased OR for EKD. Increasing HOMA was also directly correlated with higher OR for EKD, being as high as 3.89 (95% CI, 1.99-7.59) for subjects in the fourth quartile. Subjects with the syndrome plus EKD showed an increased intima-media thickness compared with those without kidney disease. CONCLUSIONS: Insulin resistance and all metabolic syndrome traits except low level of high-density lipoproteins were significantly associated with an increased OR for EKD. Both metabolic syndrome and EKD were independently and additively related to the presence of surrogate markers of arteriosclerosis

Targeted nanoparticles towards increased L cell stimulation as a strategy to improve oral peptide delivery in incretin-based diabetes treatment

The delivery of therapeutic peptides via the oral route remains one of biggest challenges in the pharmaceutical industry. Recently, we have described an alternative improved drug delivery system for peptide delivery via the oral route, consisting of a lipidic nanocapsule. Despite the striking effects observed, it is still essential to develop strategies to strengthen the nanocarriers' glucagon-like peptide-1 (GLP-1) secretory effect of the nanocarrier and/or prolong its antidiabetic effect in vivo to facilitate its translation into the clinic. For this purpose, we developed and compared different fatty acid-targeted lipid and polymeric nanoparticles and evaluated the L cell stimulation induced by the nanocarriers in murine L cells in vitro and in normal healthy mice in vivo. We further examined the antidiabetic effect in vivo in an obese/diabetic mouse model induced by high-fat diet feeding and examined the effect of the oral administration frequency. Among the tested nanocarriers, only lipid-based nanocarriers that were surface-modified with DSPE-PEG(2000) on the surface were able to significantly strengthen the biological effect of the nanocarriers. They increased endogenous GLP-1 levels up to 8-fold in vivo in normo-glycemic mice. Moreover, they effectively prolonged the in vivo antidiabetic effect by normalizing the plasma glucose levels in obese/diabetic mice following long-term treatment (one month). Ultimately, the targeted nanocarriers were as effective when the administration frequency was reduced from once daily to once every other day

A simple route to highly active single-enzyme nanogels

Just add sugar: the synthesis of single-enzyme nanogels, a class of highly robust nanobiocatalysts, is boosted by the addition of carbohydrates. Our methodology is demonstrated with a dozen commercial proteins, spanning a large size interval and a broad domain of applications. In addition, new in-depth structural characterizations are provided.</p

NADPH Oxidase–Dependent Superoxide Production Is Associated With Carotid Intima-Media Thickness in Subjects Free of Clinical Atherosclerotic Disease

Objective—Oxidative stress plays a critical role in the pathogenesis of atherosclerosis. The NADPH oxidase constitutes the main source of superoxide in phagocytic and vascular cells. This study aimed to investigate the levels of NADPH oxidase–mediated superoxide production in phagocytic cells and the association between phagocytic superoxide production and carotid intima-media thickness (IMT), a surrogate marker of asymptomatic atherosclerosis. Methods and Results—NADPH oxidase–mediated superoxide production was determined by a chemiluminescence assay using lucigenin and associated with IMT for 184 asymptomatic subjects free of overt clinical atherosclerotic disease. Compared with individuals in the lowest tertile of superoxide production, those in the upper tertile ( 20 counts/sec) showed significantly higher IMT (P 0.05). In correlation analysis, a positive relationship was found between superoxide production and carotid IMT. Superoxide production also correlated positively (P 0.05) with body mass index (BMI). In multivariate analysis, the association of superoxide production with carotid IMT remained significant after adjustment for age, sex, systolic blood pressure, BMI, triglycerides, glucose, and smoking. Conclusions—In a population sample of adults without clinically overt atherosclerotic disease, increased NADPH oxidase activity was associated with enhanced carotid IMT, suggesting a relationship between phagocytic NADPH oxidase– mediated oxidative stress and the development of atherosclerosis