A Method for Rapid Screening of Anilide-Containing AMPK Modulators Based on Computational Docking and Biological Validation

Adenosine 5′-monophsphate-activated protein kinase (AMPK) is a crucial energy sensor for maintaining cellular homeostasis. Targeting AMPK may provide an alternative approach in treatment of various diseases like cancer, diabetes, and neurodegenerations. Accordingly, novel AMPK activators are frequently identified from natural products in recent years. However, most of such AMPK activators are interacting with AMPK in an indirect manner, which may cause off-target effects. Therefore, the search of novel direct AMPK modulators is inevitable and effective screening methods are needed. In this report, a rapid and straightforward method combining the use of in silico and in vitro techniques was established for selecting and categorizing huge amount of compounds from chemical library for targeting AMPK modulators. A new class of direct AMPK modulator have been discovered which are anilides or anilide-like compounds. In total 1,360,000 compounds were virtually screened and 17 compounds were selected after biological assays. Lipinski’s rule of five assessment suggested that, 13 out of the 17 compounds are demonstrating optimal bioavailability. Proton acceptors constituting the structure of these compounds and hydrogen bonds with AMPK in the binding site appeared to be the important factors determining the efficacy of these compounds

Attitudes and perceptions about clinical guidelines: a qualitative study with Spanish physicians

Estudio cuyo objetivo es la evaluación de las actitudes y percepciones los médicos españoles con relación las Guías de práctica clínica. Spanish physicians towards CGs

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Developmental regulation of a proinsulin messenger RNA generated by intron retention

Proinsulin gene expression regulation and function during early embryonic development differ remarkably from those found in postnatal organisms. The embryonic proinsulin protein content decreased from gastrulation to neurulation in contrast with the overall proinsulin messenger RNA increase. This is due to increasing levels of a proinsulin mRNA variant generated by intron 1 retention in the 5′ untranslated region. Inclusion of intron 1 inhibited proinsulin translation almost completely without affecting nuclear export or cytoplasmic decay. The novel proinsulin mRNA isoform expression was developmentally regulated and tissue specific. The proportion of intron retention increased from gastrulation to organogenesis, was highest in the heart tube and presomitic region, and could not be detected in the pancreas. Notably, proinsulin addition induced cardiac marker gene expression in the early embryonic stages when the translationally active transcript was expressed. We propose that regulated unproductive splicing and translation is a mechanism that regulates proinsulin expression in accordance with specific requirements in developing vertebrates

The Calcium-Induced Regulation in the Molecular and Transcriptional Circuitry of Human Inflammatory Response and Autoimmunity

Rheumatoid arthritis synovial fibroblasts (RASFs) are fundamental effector cells in RA driving the joint inflammation and deformities. Celastrol is a natural compound that exhibits a potent anti-arthritic effect promoting endoplasmic reticulum (ER) stress mediated by intracellular calcium (Ca2+) mobilization. Ca2+ is a second messenger regulating a variety of cellular processes. We hypothesized that the compound, celastrol, affecting cytosolic Ca2+ mobilization could serve as a novel strategy to combat RA. To address this issue, celastrol was used as a molecular tool to assay the inflammatory gene expression profile regulated by Ca2+. We confirmed that celastrol treatment mobilized cytosolic Ca2+ in patient-derived RASFs. It was found that 23 genes out of 370 were manipulated by Ca2+ mobilization using an inflammatory and autoimmunity PCR array following independent quantitative PCR validation. Most of the identified genes were downregulated and categorized into five groups corresponding to their cellular responses participating in RA pathogenesis. Accordingly, a signaling network map demonstrating the possible molecular circuitry connecting the functions of the products of these genes was generated based on literature review. In addition, a bioinformatics analysis revealed that celastrol-induced Ca2+ mobilization gene expression profile showed a novel mode of action compared with three FDA-approved rheumatic drugs (methotrexate, rituximab and tocilizumab). To the best of our knowledge, this is a pioneer work charting the Ca2+ signaling network on the regulation of RA-associated inflammatory gene expression

Anales de Edafología y Agrobiología Tomo 44 Número 7-8

l. Suelos. Física Nuevo método para estimar la evapotranspiración potencial y el déficit de precipitación. Fórmulas para Salamanca y Zamora, por F. de Pablo, A. Egido, L. J. Rivas y J. Garmendia.-- Estudio climatológico del Valle del Guadalquivir mediante un modelo vectorial (Análisis de componentes generalizado), por R. Roman y M. C. Navarro. l. Suelos. Química Alfisoles de los Montes de Toledo. III. Perfil ultic palexeralf. Estudio mineralógico de la fracción arcilla por difracción de Rayos X y espectroscopia infrarroja, por P. Recio y M. T. García-González.-- Alfisoles de los Montes de Toledo. IV. Perfil ultic palexeralf. Estudio mineralógico de la fracción arcilla por métodos térmicos de análisis. Determinaciones analíticas elementales, por P. Recio y M. T. García-González.-- Determinación de la actividad fosfatasa en suelos gallegos. Precisiones al método de Sarathchandra y Perrot, por Ma C. Trasar Cepeda, F. Gil Sotres y F. Guitián Ojea.--Contribución al estudio de la movilización de nitrógeno en ecosistemas del centro de España, por A. García-Villaraco y F. Velasco de Pedro-- Movilización y fijación biológica de cationes en ecosistemas forestales. l. Dinámica del Ca y Mg en los horizontales superficiales del suelo, por A. García-Vilaraco.-- Electromelioration of saline-alkali soils • a review, by L. L. Somanil.-- Suelos.-Biologfa Efectos de la deforestación sobre los suelos de la comarca de Antequera (Málaga).lll. Análisis y evaluación, por R. Delgado Calvo-Flores, G. Barceló y J. Párraga.-- l. Suelos-Génesis, Clasificación y Cartografía Los xerumbrepts bajo matorral de alta montaña de la vertiente sur de Sierra Nevada (Granada), por G. Delgado Calvo-Flores, J. Párraga Martínez, E. Serrano Molina y R. Delgado Calvo-Flores.-- Aplicación de un análisis multivariante a los suelos de la Alfaguara (Sierra de Alfacar• Granada), por l. García Fernández, M. Simón Torres, A. Polo Sánchez.-- l. Suelos. Fertilidad Presence and characterization of micrococcus luteus in a bare soil, by M. A. Sagardoy.-- Soil managements and use of 15 N-Labelled fertilizer for weat in semiarid Argentina. 2, por R. A. Rosell, R. M. Martínez y K. Ch. Sommer.-- Contribución al conocimiento de la utilización del agua del suelo por las especies fores• tales (Quercus robus y Pinus pinaster) bajo clima templado húmedo, por A. Paz González y F. Díaz-Fierros Viqueira.-- Fertilizer and foliar sampling trials in two stages of development of the flower bud in the rose 'Mercedes', by C. E. Alvarez, M. Fernández, V. García and A. E. Carracedo.-- Poder fertilizante de los lodos residuales: efecto sobre el contenido total y disponibilidad de Fe, Mn, Cu, Co y Ni, por M. L. Andrade Couce, A. M ateos Beato y F. Guitián Ojea.-- Adición de lodos residuales a un suelo ácido : influencia sobre el contenido total, disponi• bilidad y absorción por el cultivo, de Zn, Pb, Cr y Cd, por M. L.Andrade Couce, M. Bao Iglesias y F. Guitián Ojea.—II. Biología Vegetal.-Nutrición Estudio comparativo de metodologías de control nutricional en plantas de pimiento cul• tivadas en invernadero bajo sistema de riego localizado, por C. F. Alcaraz, M. •A. Martínez-Cañadas, F. Martínez-Sánchez y F. Sevilla. II. Biología Vegetal. Fisiología Inducción y cultivo de callos procedentes de explantes de hipocotilo, cotiledon y ra• dicula de Erysimum scoparium, por J. F. Pérez Francés, F. Valdés, A. J. Carmona y A. C. Blesa.-- Biología Vegetal. Agrobiologfa Diversidad florística y heterogeneidad ambiental en una dehesa de Sierra Morena, por T. Marañón Arana.-- Trabajo recapitulativo Revisión monográfica de la aplicación de técnicas de microanálisis de Rayos-X en Viología Vegetal, por J. M. Pozuelo y M. R. de Felipe. BibliografíaPeer reviewe