Model and neural control of the depth of anesthesia during surgery

At present, the experimentation of anesthetic drugs on patients requires a regulation protocol, and the response of each patient to several doses of entry drug must be well known. Therefore, the development of pharmacological dose control systems is a promising field of research in anesthesiology. In this paper it has been developed a non-linear compartmental pharmacokinetic-pharmacodynamical model which describes the anesthesia depth effect on a sufficiently reliable way over a set of patients with the depth effect quantified by the Bi-Spectral Index. Afterwards, an Artificial Neural Network (ANN) predictive controller has been designed based on the depth of anesthesia model so as to keep the patient on the optimum condition while he undergoes surgical treatment. For the purpose of quantifying the efficiency of the neural predictive controller, a classical proportional-integral-derivative controller has also been developed to compare both strategies. Results show the superior performance of predictive neural controller during Bi- Spectral Index reference tracking.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Spatial and Temporal Protein Modules Signatures Associated with Alzheimer Disease in 3xTg-AD Mice Are Restored by Early Ubiquinol Supplementation

Despite its robust proteopathic nature, the spatiotemporal signature of disrupted protein modules in sporadic Alzheimer's disease (AD) brains remains poorly understood. This considered oxidative stress contributes to AD progression and early intervention with coenzyme Q10 or its reduced form, ubiquinol, delays the progression of the disease. Using MALDI-MSI and functional bioinformatic analysis, we have developed a protocol to express how deregulated protein modules arise from hippocampus and cortex in the AD mice model 3xTG-AD in an age-dependent manner. This strategy allowed us to identify which modules can be efficiently restored to a non-pathological condition by early intervention with ubiquinol. Indeed, an early deregulation of proteostasis-related protein modules, oxidative stress and metabolism has been observed in the hippocampus of 6-month mice (early AD) and the mirrored in cortical regions of 12-month mice (middle/late AD). This observation has been validated by IHC using mouse and human brain sections, suggesting that these protein modules are also affected in humans. The emergence of disrupted protein modules with AD signature can be prevented by early dietary intervention with ubiquinol in the 3xTG-AD mice model.A pesar de su robusta naturaleza proteopática, la firma espaciotemporal de los módulos de proteínas interrumpidos en los cerebros de la enfermedad de Alzheimer (EA) esporádica sigue siendo poco conocida. Este considerado estrés oxidativo contribuye a la progresión de la EA y la intervención precoz con coenzima Q10 o su forma reducida, el ubiquinol, retrasa la progresión de la enfermedad. Usando MALDI-MSI y análisis bioinformático funcional, hemos desarrollado un protocolo para expresar cómo surgen módulos de proteína desregulados del hipocampo y la corteza en el modelo de ratones AD 3xTG-AD de una manera dependiente de la edad. Esta estrategia nos permitió identificar qué módulos se pueden restaurar de manera eficiente a una condición no patológica mediante una intervención temprana con ubiquinol. De hecho, una desregulación temprana de los módulos proteicos relacionados con la proteostasis, Se ha observado estrés oxidativo y metabolismo en el hipocampo de ratones de 6 meses (EA temprana) y se refleja en regiones corticales de ratones de 12 meses (EA media/tardía). Esta observación ha sido validada por IHC utilizando secciones de cerebro humano y de ratón, lo que sugiere que estos módulos de proteína también se ven afectados en humanos. La aparición de módulos de proteínas interrumpidos con la firma AD puede prevenirse mediante una intervención dietética temprana con ubiquinol en el modelo de ratones 3xTG-AD

CoQ10 reduces glioblastoma growth and infiltration through proteome remodeling and inhibition of angiogenesis and inflammation

Purpose: Most monotherapies available against glioblastoma multiforme (GBM) target individual hallmarks of this aggressive brain tumor with minimal success. In this article, we propose a therapeutic strategy using coenzyme Q10 (CoQ10) as a pleiotropic factor that crosses the blood-brain barrier and accumulates in cell membranes acting as an antioxidant, and in mitochondrial membranes as a regulator of cell bioenergetics and gene expression. Methods: Xenografts of U251 cells in nu/nu mice were used to assay tumor growth, hypoxia, angiogenesis, and inflammation. An orthotopic model was used to explore microglial infiltration, tumor growth, and invasion into the brain parenchyma. Cell proliferation, migration, invasion, proteome remodeling, and secretome were assayed in vitro. Conditioned media were used to assay angiogenesis, monocyte chemoattraction, and differentiation into macrophages in vitro. Results: CoQ10 treatment decreased tumor volume in xenografts and orthotopic models, although its effect on tumor cell proliferation was not direct. Tumors from mice treated with CoQ10 were less hypoxic and vascularized, having less infiltration from inflammatory cells. Treatment-induced downregulation of HIF-1α and NF-kB led to a complete remodeling of the tumor cells proteome and secretome, impacting angiogenesis, monocyte infiltration, and their differentiation into macrophages. Besides, tumor cell migration and invasion were drastically restricted by mechanisms involving modulation of the actin cytoskeleton and downregulation of matrix metalloproteases (MMPs). Conclusions: CoQ10 has a pleiotropic effect on GBM growth, targeting several hallmarks simultaneously. Thus, its integration into current treatments of this fatal disease should be considered. Keywords: Angiogenesis; Coenzyme Q10; Glioblastoma; Inflammation; Invasion.Propósito: La mayoría de las monoterapias disponibles contra el glioblastoma multiforme (GBM) se dirigen a las características individuales de este tumor cerebral agresivo con un éxito mínimo. En este artículo proponemos una estrategia terapéutica utilizando la coenzima Q 10 (CoQ 10 ) como factor pleiotrópico que atraviesa la barrera hematoencefálica y se acumula en las membranas celulares actuando como antioxidante, y en las membranas mitocondriales como regulador de la bioenergética celular y gen expresión. Métodos: Se utilizaron xenoinjertos de células U251 en ratones nu/nu para analizar el crecimiento tumoral, la hipoxia, la angiogénesis y la inflamación. Se utilizó un modelo ortotópico para explorar la infiltración microglial, el crecimiento tumoral y la invasión del parénquima cerebral. Se ensayaron in vitro la proliferación celular, la migración, la invasión, la remodelación del proteoma y el secretoma. Se usaron medios acondicionados para analizar la angiogénesis, la quimioatracción de monocitos y la diferenciación en macrófagos in vitro. Resultados: el tratamiento con CoQ 10 disminuyó el volumen tumoral en xenoinjertos y modelos ortotópicos, aunque su efecto sobre la proliferación de células tumorales no fue directo. Los tumores de ratones tratados con CoQ 10 eran menos hipóxicos y vascularizados, con menos infiltración de células inflamatorias. La regulación a la baja inducida por el tratamiento de HIF-1α y NF-kB condujo a una remodelación completa del proteoma y el secretoma de las células tumorales, lo que impactó en la angiogénesis, la infiltración de monocitos y su diferenciación en macrófagos. Además, la migración e invasión de células tumorales se vieron drásticamente restringidas por mecanismos que involucran la modulación del citoesqueleto de actina y la regulación a la baja de las metaloproteasas de matriz (MMP). Conclusiones: CoQ 10 tiene un efecto pleiotrópico en el crecimiento de GBM, apuntando a varios sellos simultáneamente. Por lo tanto, se debe considerar su integración en los tratamientos actuales de esta enfermedad mortal

The Protective Effect of Ubiquinone against the Amyloid Peptide in Endothelial Cells Is Isoprenoid Chain Length-Dependent

Vascular brain pathology constitutes a common feature in neurodegenerative diseases that could underlie their development. Indeed, vascular dysfunction acts synergistically with neurodegenerative changes to exacerbate the cognitive impairment found in Alzheimer’s disease. Different injuries such as hypertension, high glucose, atherosclerosis associated with oxidized low-density lipoprotein or inflammation induce NADPH oxidase activation, overproduction of reactive oxygen species, and apoptosis in endothelial cells. Since it has been shown that pretreatment of cultured endothelial cells with the lipophilic antioxidant coenzyme Q10 (CoQ10) displays a protective effect against the deleterious injuries caused by different agents, this study explores the cytoprotective role of different CoQs homologues against Aβ25–35-induced damage and demonstrates that only pretreatment with CoQ10 protects endothelial brain cells from Aβ25–35-induced damage. Herein, we show that CoQ10 constitutes the most effective ubiquinone in preventing NADPH oxidase activity and reducing both reactive oxygen species generation and the increase in free cytosolic Ca2+ induced by Aβ25–35, ultimately preventing apoptosis and necrosis. The specific cytoprotective effect of CoQ with a side chain of 10 isoprenoid units could be explained by the fact that CoQ10 is the only ubiquinone that significantly reduces the entry of Aβ25–35 into the mitochondria

Study of <i>Salmonella</i> spp. from Cage Papers Belonging to Pet Birds in an Argentinean Canary Breeder Championship

Birds, including canaries and other birds, have become increasingly popular as pets. Bird fairs, where breeders gather and show their production in a championship setting, present a setting for possible Salmonella spp. contamination and transmission. Therefore, this study estimated the rate of Salmonella spp. isolation from cage papers, located in the bottom of cages of exotic pet birds, including canaries. Collected Salmonella isolates were used to determine the antimicrobial resistance profile to 52 antibiotics and 17 commercial disinfectants, based on pure or a mixture of acids, alcohols, aldehydes, alkalis, halogens, peroxygen, and quaternary ammonium compounds. The samples consisted of 774 cage papers taken in the 2015 Argentinean canary breeder championship, pooling three cage papers into one sterile sampling bag. Only one pool of the cage papers was positive for Salmonella spp. (0.4%), which belonged to the sample from three frill canary cages. Two strains of Salmonella serotype Glostrup were isolated, which were only resistant to sulfonamides and erythromycin and sensitive to alkali-based product PL301 AS. Although the rate of Salmonella spp. isolation from cage papers in an Argentinean canary breeder championship is low, it should not be discounted because Salmonella ser. Glostrup can be a source of human Salmonella outbreaks and they show high resistance to disinfecting products