Molecular dynamics of structural effects of reactive carbonyl species derivate of lipid peroxidation on bovine serum albumin.

BACKGROUND: Serum albumin is the most abundant protein in the Mammalia blood plasma at where plays a decisive role in the transport wide variety of hydrophobic ligands. BSA undergoes oxidative modifications like the carbonylation by the reactive carbonyl species (RCSs) 4-hydroxy-2-nonenal (HNE), 4 hydroxy-2-hexenal (HHE), malondialdehyde (MDA) and 4-oxo-2-nonenal (ONE), among others. The structural and functional changes induced by protein carbonylation have been associated with the advancement of neurodegenerative, cardiovascular, metabolic and cancer diseases. METHODS: To elucidate structural effects of protein carbonylation with RCSs on BSA, parameters for six new non-standard amino acids were designated and molecular dynamics simulations of its mono­carbonylated-BSA systems were conducted in the AMBER force field. Trajectories were evaluated by RMSD, RMSF, PCA, RoG and SASA analysis. RESULTS: An increase in the conformational instability for all proteins modified with local changes were observed, without significant changes on the BSA global three-dimensional folding. A more relaxed compaction level and major solvent accessible surface area for modified systems was found. Four regions of high molecular fluctuation were identified in all modified systems, being the subdomains IA and IIIB those with the most remarkable local conformational changes. Regarding essential modes of domain movements, it was evidenced that the most representatives were those related to IA subdomain, while IIIB subdomain presented discrete changes. CONCLUSIONS: RCSs induces local structural changes on mono­carbonylated BSA. Also, this study extends our knowledge on how carbonylation by RCSs induce structural effects on proteins.

Hábitos de consumo de medicamentos de venta libre por estudiantes del área de la salud en Cartagena-Colombia / Over-the-counter medication consumption habits in health students from Cartagena-Colombia / Hábitos de consumo de medicamentos isentos de prescrição por estudantes de saúde em Cartagena-Colômbia

Introducción: Los medicamentos de venta libre (OTC por su sigla en inglés Over The Counter), son ampliamente usados por la mayoría de las personas a nivel mundial, sin embargo, solamente son usados de forma responsable en países donde existe una farmacia comunitaria profesional legalizada. Objetivo: Describir los hábitos de consumo de medicamentos de venta libre por estudiantes universitarios del área de la salud. Materiales y métodos: Estudio descriptivo transversal, desarrollado en tres universidades de Cartagena. Se aplicó un instrumento tipo encuesta a 140 estudiantes acerca de hábitos de consumo y conocimiento sobre OTC, creencias, actitudes y prácticas. Resultados: El cuestionario presentó una consistencia interna alta con Alfa de Cronbach'sde 0,77. El 59% fueron mujeres, las en edades entre 16-30 años, el 91% estuvo de acuerdo que la automedicación es perjudicial. Sin embargo, 61% asegura automedicarse porque los padecimientos son menores y frecuentes. Los medicamentos de mayor consumo, fueron el acetaminofén 52,9% y los medicamentos antiinflamatorios no esteroides (AINES) con 16,48%, incluyeron en sus respuestas medicamentos de no venta libre. Conclusión: Los estudiantes son conscientes del riesgo de la automedicación, sin embargo, la practican de forma frecuente. Muchos reportaron consumo de medicamentos como amitriptilina, antibióticos, opiáceos, furosemida y corticoides.

Introduction: Over-the-counter (OTC) medications are widely used worldwide, however they are responsibly used only in countries with legalized professional community pharmacies. Objective:To describe over-the-counter medication use habits in university students from health programs. Materials and methods:Descriptive cross-sectional study carried out in three universities from Cartagena. A survey-type instrument was applied to 140 students, asking about their use habits and knowledge regarding OTC, beliefs, attitudes and practices. Results:The questionnaire showed a high internal inconsistency, with a Cronbach's alpha of 0.77. 59% of participants were women aged between 16 to 30 years old and 91% agreed that self-medication is harmful. Nevertheless, 61% self-medicated because of minor and frequent conditions. OTC medications with the highest use were acetaminophen (52.9%) and NSAIDs (16.48%). Conclusions:Even though students are aware of the self-medication risks, they still practice it frequently. Many participants reported the use of medications such as amitriptyline, antibiotics, opioids, furosemide, and corticosteroids.

Introdução:Os medicamentos isentos de prescrição (OTCOver The Counter) são amplamente utilizados pela maioria das pessoas em todo o mundo, porém somente são usados de forma responsável em países onde existe uma farmácia comunitária profissional legalizada. Objetivo: Descrever os hábitos de consumo de medicamentos isentos de prescrição por universitários da área da saúde. Materiais e métodos: Estudo descritivo transversal, desenvolvido em três universidades de Cartagena. Foi aplicado um instrumento do tipo inquérito a 140 alunos sobre hábitos de consumo e conhecimentos sobre OTC, crenças, atitudes e práticas. Resultados: O questionário apresentou alta consistência interna com Alfa de Cronbach ́sde 0,77. 59% eram mulheres, com idades entre 16 e 30 anos, 91% concordaram que a automedicação é prejudicial. No entanto, 61% dizem que se automedicam porque os males são leves e frequentes. Os medicamentos de maior consumo foram o acetaminofeno 52,9% e os anti-inflamatórios não esteroidais com 16,48%, incluindo medicamentos isentos de prescrição em suas respostas. Conclusão: Os alunos estão cientes do risco da automedicação, porém isto é praticado com frequência. Muitos relataram consumo de medicamentos como amitriptilina, antibióticos, opioides, furosemida e corticosteroides.

In-silico study for the identification of potential destabilizers between the spike protein of SARS-CoV-2 and human ACE-2.

The emergence of the new SARS-CoV-2 virus, which causes the disease known as COVID-19, has generated a pandemic that has plunged the world into a health crisis. The infection process is triggered by the direct binding of the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) of the host cell. In the present study, virtual screening techniques such as molecular docking, molecular dynamics, calculation of free energy using the GBSA method, prediction of drug similarity, pharmacokinetic, and toxicological properties of various ligands interacting with the RBD-ACE2 complex were applied. The ligands radotinib, hinokiflavone, and ginkgetin were identified as potential destabilizers of the RBD-ACE2 interaction, which could produce their pharmacological effect by interacting at an allosteric site of ACE2, with affinity energy values of -10.2 ± 0.1, -9.8 ± 0.0, and -9.4 ± 0.0 kcal/mol, indicating strong receptor affinity. The complex with hinokiflavone showed the highest conformational stability and rigidity of the dynamic simulation and also obtained the best binding free energy of the three molecules, with an energy of -215.86 kcal/mol.

Cysteine carbonylation with reactive carbonyl species from lipid peroxidation induce local structural changes on thioredoxin active site.

Protein oxidative modifications with reactive carbonyl species (RCS) is directly linked to metabolic processes in premature aging, cancer, neurodegenerative and infectious diseases. RCS as 4-Hydroxy-2-nonal (HNE), 4-Hydroxy-2-hexenal (HHE), 4-Oxo-2-nonenal (ONE) and Malondialdehyde (MDA) attack nucleophilic amino acids residues forming irreversible adducts with proteins as Thioredoxins (Trx). This is a class of small thiol oxide-reductases playing a key role in redox signaling and oxidative stress responses in mammals. Although proteomic studies have identified to Cys-32 residue as a target of HNE attack that inhibit its enzymatic activity, how this carbonylation affects its structure and dynamic behavior at the atomic level is unknown. Even more, the molecular bases for the atomistic behavior of these modified proteins have not been completely understood. We present molecular dynamics simulations of Trx-modified with four different RCS to analyze its global and local structural effects. For this, parameters supported in the AMBER force fields were built and validated for three non-natural cysteine residues modified with HHE, ONE and MDA. Results obtained showed a slight change in the global conformational stability of Trx modified with HNE and MDA, establishing that all modified proteins presented local regions of high mobility in the modified catalytic site and some regions far from the modification area. In addition, essential domain movement modes evidences that proteins modified with the RCS assayed induce changes in conformational flexibility. Finally, these data showed that the given conformational changes did not caused global changes in proteins but rather localized changes in particular regions.

Bioinformatic Analysis of Plus Gene Expression Related to Progression from Leukoplakia to Oral Squamous Cell Carcinoma.

INTRODUCTION: Leukoplakia is one of the most frequently found lesions in the oral cavity, with a probability of 17 to 24% of becoming malignant cells in a period of 30 years. OBJECTIVE: To identify differentially expressed gene profiles of leukoplakia and its progression to oral squamous cell carcinoma, essential for the discovery of new biomarkers to predict and prevent the presence of diseases in the oral cavity. METHODS: Initially, gene profiles of GSE85514 and GSE160042 from the Gene Expression Omnibus database were used. Differentially expressed genes were identified using GEO2R. The CLUEGO plugin in Cytoscape was used for DEG functionality and enrichment analysis. Finally, a protein-protein interaction (PPI) network was constructed using Cytoscape from data collected online from the STRING server. RESULTS: According to the MCC algorithm, the 10 most found gene sequences were HNRNPU, SMC1A, PAFAH1B1, EHMT1, SPTBN4, OLFM1, NCAM1, SF3B3, FGF2, and UBE2I; with HNRNPU, SMC1A, and PAFAH1B1 being the most representative of the modules. CONCLUSIONS: We were able to describe the gene sequences that promote the progression from leukoplakia to oral squamous cell carcinoma. Within these genes, the HNRNPU, SMC1A, and PAFAH1B1 constitute the main promising therapeutic targets to counteract the progression of oral cancer, they could also be important biomarkers for the diagnosis and classification of the disease.

AMBER parameters and topology data of 2-pentylpyrrole adduct of arginine with 4-hydroxy-2-nonenal.

The data described here supports a part of the research article "Effect of 4­HNE Modification on ZU5-ANK Domain and the Formation of Their Complex with ß­Spectrin: A Molecular Dynamics Simulation Study" [1]. Dataset on Gaff force field parameters of AMBER is provided for the non-standard arginine resulting of reaction with 4-hydroxy-2-nonenal (4-HNE), the major secondary product of lipids peroxidation. Arg-HNE 2-pentilpyrrole adduct is part of the 4-hydroxyalkenals described in various physiopathological disorders related to increased oxidative stress. Data include a framework for derivation of missing bonds, angles and dihedral parameters for modified arginine, alongside optimized partial charges derived with Restrained Electrostatic Potential (RESP) method and the new force field parameters obtained by quantum mechanicals methods (QM) using Hartree-Fock (HF)/6 - 31G** level of theory. Benchmark as a graphics tutorial summary steps to obtained new parameters and the validation of non-standard amino acids is presented. The new residue constructed is put available to the scientific community to perform molecular dynamics simulations of modified 4-HNE proteins on arginine residue and complete the set of data parameters for nucleophilic residues with this reactive aldehyde ADDIN EN.CITE ADDIN EN.CITE.DATA [2]. Data that could be used for the researchers interested in the role of protein oxidation as mediator in cellular pathophysiological.

Effect of 4-HNE Modification on ZU5-ANK Domain and the Formation of Their Complex with ß-Spectrin: A Molecular Dynamics Simulation Study.

4-HNE-modified ankyrins have been described in diseases such as diabetes, renal failure, G6PD deficient, sickle cell trait, and P. falciparum infected erythrocytes with different AB0 blood groups. However, effects at the atomic level of this carbonylation on structure and function of modified protein are not yet fully understood. We present a study based on molecular dynamics simulations of nine 4-HNE modified residues of the ZU5-ANK ankyrin domain with ß-spectrin and their binding energy profiles. Results show that 4-HNE induced local conformational changes over all protein systems evaluated, increased mobility in the modification sites, and localized structural changes between the positively charged patch of the ZU5-ANK domain. Carbonylation with 4-HNE on lysine residues decreased the affinity between ZU5-ANK and the 14-ß-spectrin repeat by reducing electrostatic and van der Waals interactions. The presented work provides further insight into understanding the loss of human erythrocyte deformation capacity under conditions of oxidative stress in different diseases.

4-HNE carbonylation induces local conformational changes on bovine serum albumin and thioredoxin. A molecular dynamics study.

4-hydroxy-2-nonenal (4-HNE) is the main end product of peroxidation in lipids, capable of introduce carbonyl groups to nucleophilic amino acids via Michael additions and alter protein function. It has been reported that 4-HNE protein carbonylation is associated with intracellular protein aggregation, the pathogenesis of neurodegenerative and metabolic diseases and yet it is unclear how the carbonylation affects the protein structure and dynamics at the atomic level. Here, we analysis the structural effects of 4-HNE modification through formation of Michael adducts of Cys-4HNE, His-4HNE and Lys-4HNE on Serum Albumin (BSA) and Thioredoxin (TRX). Since both proteins have experimental evidence to possess 4-HNE-modifications on cysteine, histidine and lysine residues, extended molecular dynamics simulations were performed with AMBER to study the carbonylation effects in the structure of these proteins. BSA is the main protein of plasma while TRX is an important antioxidant enzyme. Results showed local changes and alteration in the conformational stability, folding and flexibility after including the 4-HNE modification. DSSP analysis showed important structural modifications as a consequence of the inclusion of the modified residues. Analysis of the computed trajectories suggests that 4-HNE decreases stability, increases local flexibility and produced modest unfolding on both tested proteins. Finally, all the systems evaluated shown an increase in the lipophilic potential and a modest decrease in the electrostatic potential in BSA but an increase in TRX.

Prevalencia de infección del tracto urinario, uropatógenos y perfil de susceptibilidad en un hospital de Cartagena, Colombia. 2016 / Prevalence of urinary tract infection, uropathogens and susceptibility profile in a hospital of Cartagena-Colombia in 2016

Resumen Introducción. Dada la alta prevalencia de la infección del tracto urinario (ITU) y la significativa resistencia de los patógenos implicados, el mundo se enfrenta a un problema creciente de salud pública. Objetivos. Describir la prevalencia de ITU y uropatógenos y analizar los perfiles de susceptibilidad en los reportes de urocultivos del laboratorio de microbiología de un hospital de referencia. Materiales y métodos. Se llevó a cabo un estudio transversal con una muestra de 396 urocultivos positivos en el que se calculó la prevalencia de ITU, uropatógenos y perfil de resistencia microbiana. Se realizaron pruebas de hipótesis y regresión logística no condicional para conocer si existía diferencia estadística entre el género. Resultados. La prevalencia de ITU fue del 28%, los tres patógenos aislados más frecuentes fueron Escherichia coli, Escherichia. coli con β-lactamasas de espectro extendido y Pseudomonas. aeruginosa. La mayor frecuencia de resistencia a antibióticos para estos patógenos fue ampicilina (66.6%), ceftriaxona (100%) y gentamicina (39.5%), respectivamente. Conclusiones. Por la alta prevalencia, el amplio espectro de uropatógenos aislados y la diversidad de perfiles de resistencia antibiótica, se evidencia la necesidad de desarrollar investigaciones locales que permitan orientar las acciones en salud y vigilancia epidemiológica.

Abstract Introduction: Given the high prevalence of urinary tract infection (UTI) and the significant resistance of the pathogens involved, the world faces a growing public health issue. More studies are needed to analyze microbial susceptibility profiles. Objectives: To describe the prevalence of UTIs and uropathogens and to analyze the susceptibility profiles of urine samples of the microbiology laboratory of a reference hospital. Materials and methods: A cross-sectional study was carried out with a sample of 396 positive urine cultures, in which the prevalence of UTIs, uropathogens and microbial resistance profile was estimated. Hypothesis tests and non-conditional logistic regression tests were performed to know if there was a statistical difference between genders. Results: The prevalence of UTIs was 28%. The three most frequent isolated pathogens were Escherichia coli, Escherichia coli with extended-spectrum β-lactamases and Pseudomonas aeruginosa. The highest frequency of antibiotics resistance for these pathogens was ampicillin (66.6%), ceftriaxone (100%) and gentamicin (39.5%), respectively. Conclusions: Their high prevalence, the broad spectrum of isolated uropathogens and the diversity of antibiotic resistance profiles make evident the need to develop local research to guide health actions and epidemiological surveillance.

Development and benchmark to obtain AMBER parameters dataset for non-standard amino acids modified with 4-hydroxy-2-nonenal.

The data described here support the research article "4-HNE carbonylation induces local conformational changes on bovine serum albumin and thioredoxin. A molecular dynamics study" (Alviz-Amador et al., 2018) . Dataset on Gaff force field parameters of AMBER is provided for assembled three non-standard amino acids resulting of the 4-HNE Michael addition, the main end product of lipids peroxidation. Data include a framework for derivation of missing bonds, angles and dihedral parameters for Cys, His, and Lys modified amino acids, alongside optimized partial charges derived with Restrained Electrostatic Potential (RESP) method and the new force field parameters obtained by quantic mechanical (QM) using HF/6-31G** level of theory. Benchmark as a graphics tutorial summary steps to obtained new parameters and the validation of non-standard amino acids is presented. The new residues constructed are put available to the scientific community to perform molecular dynamics simulations of modified 4-HNE proteins.

Análisis costo-efectividad de rocuronio y succinilcolina en tiroidectomías programadas / Cost-effectiveness analisys ofrocuronium and succinylcholine in programmed thyroidectomy

RESUMEN En el presente trabajo se realiza un análisis costo-efectividad de la succinilcolina y del rocuronio utilizados en la intubación de pacientes sometidos a tiroidectomía programada, mediante un estudio descriptivo prospectivo, donde se tuvo en cuenta la calidad de intubación, los tiempos de latencia y de relajación muscular, necesidad de reversión farmacológica del bloqueo neuromuscular, parámetros hemodinámicos, reacciones adversas y costos directos e indirectos en 30 pacientes sometidos al procedimiento. El análisis económico evidenció la existencia de diferencias significativas entre los costos asociados al tiempo de latencia de la relajación muscular. En cuanto a los costos relacionados al bloqueo muscular, se observó que el grupo con succinilcolina presentó unos costos totales de 10972 ± 341,7 pesos colombianos, mientras que con rocuronio fueron de 63088 ± 1.184 con valor P < 0,0001. La succinilcolina mostró mayor costo-efectividad al presentar menor tiempo de latencia, mejores condiciones de intubación, no provocar cambios hemodinámicos clínicamente significativos y bajo costo al ser comparado con rocuronio.

SUMMARY The goal of this work was to perform a cost-effectiveness analysis of succinylcho-line and rocuronium used in the intubation of patients undergoing programmed thyroidectomy was compared by means of a prospective descriptive study, which included intubation quality, latency and muscle relaxation times, pharmacological reversion Neuromuscular blockade, hemodynamic parameters, adverse reactions and direct and indirect costs in 30 patients undergoing the procedure. The economic analysis evidenced the existence of significant differences between the costs associated with the latency time of muscle relaxation. Regarding the costs related to muscle blockade, it was observed that the succinylcholine group performed a total cost of 10972 ± 341.7 Colombian pesos, while with rocuronium it was 63088 ± 1184 with P value < 0.0001. Succinylcholine showed higher cost/effectiveness when presenting the shortest latency time, the best intubation conditions, no clinically significant cost changes and low cost when compared to rocuronium.