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Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant inherited disease characterized by progressive ataxia and retinal degeneration. SCA7 belongs to a group of neurodegenerative diseases caused by an expanded CAG repeat in the disease-causing gene, resulting in aberrant polyglutamine (polyQ) protein synthesis. PolyQ ataxin-7 is prone to aggregate in intracellular inclusions, perturbing cellular processes leading to neuronal death in specific regions of the central nervous system (CNS). Currently, there is no treatment for SCA7; however, a promising approach successfully applied to other polyQ diseases involves the clearance of polyQ protein aggregates through pharmacological activation of autophagy. Nonetheless, the blood-brain barrier (BBB) poses a challenge for delivering drugs to the CNS, limiting treatment effectiveness. This study aimed to develop a polymeric nanocarrier system to deliver therapeutic agents across the BBB into the CNS. We prepared poly(lactic-co-glycolic acid) nanoparticles (NPs) modified with Poloxamer188 and loaded with rapamycin to enable NPs to activate autophagy. We demonstrated that these rapamycin-loaded NPs were successfully taken up by neuronal and glial cells, demonstrating high biocompatibility without adverse effects. Remarkably, rapamycin-loaded NPs effectively cleared mutant ataxin-7 aggregates in a SCA7 glial cell model, highlighting their potential as a therapeutic approach to fight SCA7 and other polyQ diseases.
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Ataxias Espinocerebelares , Humanos , Ataxina-7/genética , Ataxina-7/metabolismo , Ataxias Espinocerebelares/tratamento farmacológico , Ataxias Espinocerebelares/genética , Neurônios/metabolismo , Neuroglia/metabolismo , SirolimoRESUMO
Polyamines (Pas) are short molecules that exhibit two or three amine groups that are positively charged at a physiological pH. These small molecules are present in high concentrations in a wide variety of organisms and tissues, suggesting that they play an important role in cellular physiology. Polyamines include spermine, spermidine, and putrescine, which play important roles in age-related diseases that have not been completely elucidated. Aging is a natural process, defined as the time-related deterioration of the physiological functions; it is considered a risk factor for degenerative diseases such as cardiovascular, neurodegenerative, and musculoskeletal diseases; arthritis; and even cancer. In this review, we provide a new perspective on the participation of Pas in the cellular and molecular processes related to age-related diseases, focusing our attention on important degenerative diseases such as Alzheimerߣs disease, Parkinsonߣs disease, osteoarthritis, sarcopenia, and osteoporosis. This new perspective leads us to propose that Pas function as novel biomarkers for age-related diseases, with the main purpose of achieving new molecular alternatives for healthier aging.
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Poliaminas , Espermidina , Espermina/fisiologia , PutrescinaRESUMO
Wound healing is a complex process that involves restoring the structure of damaged tissues through four phases: hemostasis, inflammation, proliferation, and remodeling. Wound dressings are the most common treatment used to cover wounds, reduce infection risk and the loss of physiological fluids, and enhance wound healing. Despite there being several types of wound dressings based on different materials and fabricated through various techniques, polymeric films have been widely employed due to their biocompatibility and low immunogenicity. Furthermore, they are non-invasive, easy to apply, allow gas exchange, and can be transparent. Among different methods for designing polymeric films, solvent casting represents a reliable, preferable, and highly used technique due to its easygoing and relatively low-cost procedure compared to sophisticated methods such as spin coating, microfluidic spinning, or 3D printing. Therefore, this review focuses on the polymeric dressings obtained using this technique, emphasizing the critical manufacturing factors related to pharmaceuticals, specifically discussing the formulation variables necessary to create wound dressings that demonstrate effective performance.
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This work proposes a combination of polyethylene glycol 400 (PEG) and trehalose as a surface modification approach to enhance PLGA-based nanoparticles as a drug carrier for neurons. PEG improves nanoparticles' hydrophilicity, and trehalose enhances the nanoparticle's cellular internalization by inducing a more auspicious microenvironment based on inhibiting cell surface receptor denaturation. To optimize the nanoprecipitation process, a central composite design was performed; nanoparticles were adsorbed with PEG and trehalose. PLGA nanoparticles with diameters smaller than 200 nm were produced, and the coating process did not considerably increase their size. Nanoparticles entrapped curcumin, and their release profile was determined. The nanoparticles presented a curcumin entrapment efficiency of over 40%, and coated nanoparticles reached 60% of curcumin release in two weeks. MTT tests and curcumin fluorescence, with confocal imaging, were used to assess nanoparticle cytotoxicity and cell internalization in SH-SY5Y cells. Free curcumin 80 µM depleted the cell survival to 13% at 72 h. Contrariwise, PEG:Trehalose-coated curcumin-loaded and non-loaded nanoparticles preserved cell survival at 76% and 79% under the same conditions, respectively. Cells incubated with 100 µM curcumin or curcumin nanoparticles for 1 h exhibited 13.4% and 14.84% of curcumin's fluorescence, respectively. Moreover, cells exposed to 100 µM curcumin in PEG:Trehalose-coated nanoparticles for 1 h presented 28% fluorescence. In conclusion, PEG:Trehalose-adsorbed nanoparticles smaller than 200 nm exhibited suitable neural cytotoxicity and increased cell internalization proficiency.
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This systematic review aimed to identify short- and long-term associated factors to functional recovery of elderly hip fracture patients after discharge. We identified 43 studies reporting 74 associated factors to functional recovery; most of them were biological, sociodemographic, or inherent factors to patients' baseline characteristics, including their pre-facture functional capacity. PURPOSE: This systematic review aimed to identify short- and long-term associated factors to functional recovery of elderly hip fracture patients after hospital discharge. We assessed the use of the hip fracture core-set and key-performance indicators for secondary fracture reduction. METHODS: A search was performed in seven electronic databases. Observational studies reporting predictors after usual care of elderly patients with hip fracture diagnoses receiving surgical or conservative treatment were included. Primary outcomes considered were part of the domains corresponding to functional capacity. RESULTS: Of 3873 references identified, and after the screening and selection process, 43 studies were included. Sixty-one functional measures were identified for ten functional outcomes, including BADLs, IADLs, ambulation, and mobility. Biological characteristics such as age, sex, comorbidities, cognitive status, nutritional state, and biochemical parameters are significantly associated. Determinants such as contact and size of social network and those related to institutional care quality are relevant for functional recovery at six and 12 months. Age, pre-fracture function, cognitive status, and complications continue to be associated five years after discharge. We found 74 associated factors to functional recovery of elderly hip fracture patients. Ten of the studies reported rehabilitation programs as suggested in KPI 9; none used the complete hip fracture core-set. CONCLUSION: Most of the associated factors for functional recovery of elderly hip fracture were biological, sociodemographic, or inherent factors to patients' baseline characteristics, including their pre-facture functional capacity. For the core-set and KPI's, we found an insufficient use and report. This study reports 61 different instruments to measure functional capacity. REGISTRATION NUMBER: PROSPERO (CRD42020149563).
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Fraturas do Quadril , Idoso , Fixação de Fratura , Fraturas do Quadril/cirurgia , Humanos , Prognóstico , Estudos Prospectivos , Recuperação de Função FisiológicaRESUMO
Seven of the most frequent spinocerebellar ataxias (SCAs) are caused by a pathological expansion of a cytosine, adenine and guanine (CAG) trinucleotide repeat located in exonic regions of unrelated genes, which in turn leads to the synthesis of polyglutamine (polyQ) proteins. PolyQ proteins are prone to aggregate and form intracellular inclusions, which alter diverse cellular pathways, including transcriptional regulation, protein clearance, calcium homeostasis and apoptosis, ultimately leading to neurodegeneration. At present, treatment for SCAs is limited to symptomatic intervention, and there is no therapeutic approach to prevent or reverse disease progression. This review provides a compilation of the experimental advances obtained in cell-based and animal models toward the development of gene therapy strategies against polyQ SCAs, providing a discussion of their potential application in clinical trials. In the second part, we describe the promising potential of nanotechnology developments to treat polyQ SCA diseases. We describe, in detail, how the design of nanoparticle (NP) systems with different physicochemical and functionalization characteristics has been approached, in order to determine their ability to evade the immune system response and to enhance brain delivery of molecular tools. In the final part of this review, the imminent application of NP-based strategies in clinical trials for the treatment of polyQ SCA diseases is discussed.
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Surfactants are essential in the manufacture of polymeric nanoparticles by emulsion formation methods and to preserve the stability of carriers in liquid media. The deposition of non-ionic surfactants at the interface allows a considerable reduction of the globule of the emulsion with high biocompatibility and the possibility of oscillating the final sizes in a wide nanometric range. Therefore, this review presents an analysis of the three principal non-ionic surfactants utilized in the manufacture of polymeric nanoparticles; polysorbates, poly(vinyl alcohol), and poloxamers. We included a section on general properties and uses and a comprehensive compilation of formulations with each principal non-ionic surfactant. Then, we highlight a section on the interaction of non-ionic surfactants with biological barriers to emphasize that the function of surfactants is not limited to stabilizing the dispersion of nanoparticles and has a broad impact on pharmacokinetics. Finally, the last section corresponds to a recommendation in the experimental approach for choosing a surfactant applying the systematic methodology of Quality by Design.
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Biomass burning from grassland, forests, and agricultural waste results in large amounts of gases and particles emitted to the atmosphere, which affect air quality, population health, crop development, and natural vegetation. Regional atmospheric circulations can transport those plumes of pollutants over hundreds of kilometers, affecting vulnerable environments such as those considered protected natural areas (PNAs). This study evaluates the spatiotemporal distribution of active fires detected, and associated emissions, in central and southern Mexico from satellite data between March and June 2017, to assess the impact of the smoke plumes on protected ecosystems. The arrival of smoke plumes to selected PNAs (both near large urban centers and in remote areas) is assessed using airmass forward trajectories from selected emission sources. The spatial distribution of the remotely derived aerosol optical depth confirms the regional impact of particle emissions from the observed fires on PNAs, particularly in central Mexico. The identified areas of high fire density are also associated with large coarse particle concentrations at the surface. Moreover, there is a significant contribution of organic carbon to the total coarse particle mass, 60% on average. Finally, while most of the impact in ambient pollution is observed in PNAs located close to the regions with active fires in southern Mexico and Central America, the long-range transport of smoke plumes reaching the USA was also confirmed.
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Poluentes Atmosféricos , Incêndios , Poluentes Atmosféricos/análise , Biomassa , Ecossistema , Monitoramento Ambiental , MéxicoRESUMO
A theoretical study was undertaken regarding the regioselective Lewis acid-promoted intramolecular cyclization of novel enaminones 1-3 leading to the corresponding benzofurans 4-5 and indoles 6. The density functional theory (DFT) and hard and soft acids and bases (HSAB) principle provided data to describe the electronic effects of the substituents in the reactivity of the benzene ring and the enaminone moiety. The condensed and local Fukui functions for nucleophilic and electrophilic attacks of the reactants accounted for the experimentally observed preference, in regard to precursors 1-3, of the cyclization between the C6' carbon (rather than the C2' carbon) of the benzene ring and the C3 center of the enaminone moiety.
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Benzofuranos/química , Indóis/química , Modelos Moleculares , Naftoquinonas/química , Ciclização , Conformação Molecular , Teoria Quântica , Análise de Regressão , Estereoisomerismo , TermodinâmicaRESUMO
In the search for new potential hypolipidemic agents, the present study focused on the synthesis of 2-acyl phenols (6a-c and 7a-c) and their saturated side-chain alkyl phenols (4a-c and 5a-c), and on the evaluation of their hypolipidemic activity using a murine Tyloxapol-induced hyperlipidemic protocol. The whole series of compounds 4-7 greatly and significantly reduced elevated serum levels of total cholesterol, LDL-cholesterol, and triglycerides, with series 6 and 7 showing the greatest potency ever found in our laboratory. At the minimum dose (25mg/kg/day), the latter compounds lowered cholesterol by 68-81%, LDL by 72-86%, and triglycerides by 59-80%. This represents a comparable performance than that shown by simvastatin. Experimental evidence and docking studies suggest that the activity of these derivatives is associated with the inhibition of HMG-CoA reductase.
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Anisóis/química , Anisóis/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fenóis/química , Fenóis/farmacologia , Derivados de Alilbenzenos , Animais , Sítios de Ligação , Domínio Catalítico , Colesterol/sangue , LDL-Colesterol/sangue , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Humanos , Hidroximetilglutaril-CoA Redutases/química , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Conformação Molecular , Simulação de Acoplamento Molecular , Ligação Proteica , Triglicerídeos/sangue , Aumento de Peso/efeitos dos fármacosRESUMO
A series of alpha-asarone-based analogues was designed by conducting docking experiments with published crystal structures of human HMG-CoA reductase. Indeed, synthesis and evaluation of this series showed a highly hypocholesterolemic in vivo activity in a murine model, as predicted by previous docking studies. In agreement with this model, the polar groups attached to the benzene ring could play a key role in the enzyme binding and probably also in its biological activity, mimicking the HMG-moiety of the natural substrate. The hypolipidemic action mechanism of these compounds was investigated by developing a simple, efficient, and novel model for determining HMG-CoA reductase inhibition. The partial purification of the enzyme from Schizosaccharomyces pombe allowed for testing of alpha-asarone- and fibrate-based analogues, resulting in positive and significant inhibitory activity.
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Anisóis/química , Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Schizosaccharomyces/efeitos dos fármacos , Derivados de Alilbenzenos , Animais , Anisóis/síntese química , Anisóis/uso terapêutico , Sítios de Ligação , Simulação por Computador , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICRRESUMO
El objetivo de esta investigación es determinar la adherencia a la guía de manejo clínico de lavado de manos por parte del personal de salud, después de la aplicación del sistema de vigilancia epidemiológica (SVE) en la unidad de cuidados intensivos (UCI) del Hospital de San José de Bogotá. Para conseguirlo se contó con un grupo de 33 individuos que conformaron la muestra. A este personal de salud se les aplicó una lista de chequeo e insumos obteniendo un diagnóstico inicial. Después se explicó el funcionamiento del SVE y se asignaron tareas. Luego se realizó un acompañamiento para solucionar inquietudes que surgieron en el diligenciamiento de las listas de verificación. A cada funcionario que labora en la UCI del Hospital de San José de Bogotá y que fue observado en el diagnóstico inicial, se le asignó un código que lo identificó de manera anónima y que lo ubicó en el semáforo epidemiológico, dependiendo del grado de adherencia de cada uno a la guía de lavado clínico de manos. Posterior a la implementación del SVE se aplicaron las mismas listas de verificación utilizadas en el diagnóstico inicial para determinar el comportamiento de la adherencia a la guía de lavado de manos, con los siguientes resultados: se observó un mejoramiento en la adherencia por parte de todo el personal de salud, donde las que menos fallaron fueron las enfermeras y las terapeutas y el número de ítems acertados llegó hasta 20, con lo cual se concluyó que el personal que labora en la UCI aunque se lava las manos, presenta deficiencias en la adherencia a la guía, las cuales son susceptibles de superarse con la aplicación continua del SVE. Aunque la práctica de lavado de manos es diaria, se deben realizar talleres de capacitación y evaluación periódica como lo estipula la guía de la Secretaría de Salud para garantizar la adherencia al 100%, pues el éxito del SVE depende de la motivación y aplicación continua por parte del personal. El control de la disponibilidad permanente de insumos, permite la exigencia del cumplimiento de la guía de manejo de lavado de manos.
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Humanos , Masculino , Feminino , Sistema de Vigilância em Saúde , Desinfecção das Mãos , Pessoal de Saúde , Unidades de Terapia IntensivaRESUMO
Se evaluó la calidad microbiológica de 92 muestras de la sección de Oncología de un Hospital Nacional, San José, Costa Rica durante los meses de febrero a julio, 2002. De éstas, 48 eran ensaladas, refrescos y frutas y 44 provenían de superficies, aire y manos del personal médico. Se determinó, mediante la técnica de recuento total, la presencia de coliformes totales y fecales utilizando Agar Bilis rojo Violeta, de Staphylococcus aureus en Agar Baird-Parker, de Pseudomonas en Agar Cetrimida y de Listeria en Caldo Universidad de Vermont, Caldo Fraizer y posteriormente aislada en Agar Oxford. El 77 por ciento de los alimentos analizados dio positivo por al menos uno de los parámetros estudiados; las frutas presentaron la mayor contaminación (94 por ciento) y las ensaladas cocinadas la menor, no obstante se determinó en éstas la presencia de Listeria (13 por ciento). El 100 por ciento de las ensaladas crudas fue positivo por coliformes fecales. Se encontró Pseudomonas y S. aureus en frutas, ensaladas crudas y refrescos. Todas las superficiales analizadas, con una excepción, resultaron negativas por los parámetros evaluados. El 75 por ciento de las manos del personal médico, dio positivo por lo menos uno de los parámetros: 25 por ciento tenía coliformes totales (2.8x10³ UFC por mano), 13 por ciento coliformes fecales (2.4x10³ UFC por mano), 69 por ciento S. aureus (1.3x10³ UFC por mano) y 19 por ciento Pseudomonas sp. Se seleccionaron al azar 115 aislamientos que se identificaron mediante pruebas miniaturalizadas (API®). Al comparar esas identificaciones con los 166 aislamientos del Laboratorio Clínico del Hospital provenientes de infecciones en los pacientes de oncología, se determinó, mediante análisis de varianza, que ambas poblaciones bacterianas eran estadísticamente semejantes
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Bactérias , Infecção Hospitalar , Microbiologia Ambiental , Contaminação de Alimentos , Serviço Hospitalar de Oncologia , Costa Rica , Microbiologia , Ciências da NutriçãoRESUMO
The microbiological quality of 92 samples from the Oncological Service of a National Hospital, San José, Costa Rica was evaluated during the months of February to July, 2002. Of these samples, 48 were from salads, refreshments, and fruits and 44 from surfaces, air and hands of the medical personnel. The presence of total and fecal coliforms was determined by the total plate count technique, using Violet Red Bile Agar for the isolation of total and fecal coliforms, Baird-Parker Agar for Staphylococcus aureus, Cetrimide Agar for Pseudomonas and Listeria was enriched in University of Vermont Broth, Fraizer Broth and isolated in Oxford Agar. From the food samples analyzed, 77% were positive for at least one of the parameters studied; the fruits presented the greater contamination (94%) and the cooked salads the minor, even though Listeria was isolated in 13% of them. All tested salads (100%) were positive for fecal coliforms. Pseudomonas and S. aureus were isolated from fruits, raw salads, and refreshments. All the analyzed surfaces, with an exception, were negative for the parameters evaluated. 75% of the hands of the medical personnel were positive for at least one of the parameters evaluated; 25% had total coliforms (2.8x10(3) UFC/hand), 13% fecal coliforms (2.4x10(3) UFC/ hand), 69% S. aureus (1.3x10(3) UFC/hand) and 19% Pseudomonas sp. 115 isolates were randomly selected, and identified using miniaturized tests (API). When comparing these identifications with the 166 isolations done at the Clinical Laboratory of the Hospital from the infected patients of oncology, by means of variance analysis, it was determined that both bacterial populations were statistically similar.
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Infecção Hospitalar/microbiologia , Inspeção de Alimentos , Microbiologia de Alimentos , Frutas/microbiologia , Serviço Hospitalar de Oncologia , Verduras/microbiologia , Microbiologia do Ar , Enterobacter/isolamento & purificação , Mãos/microbiologia , Humanos , Pseudomonas/isolamento & purificação , Staphylococcus/isolamento & purificaçãoRESUMO
Five/six nephrectomy induces systemic and glomerular hypertension, glomerulosclerosis, proteinuria, and tubulointerstitial fibrosis. Polysulfate pentosan (PPS) decreases mesangial proliferation and extracellular matrix accumulation. The aim of this study was to determine whether PPS prevents glomerular hemodynamic changes and renal damage. Micropuncture studies were performed in three groups of eight male Wistar rats. Two groups included rats with 5/6 nephrectomy-one of which was treated with PPS in drinking water (100 mg/kg body wt) and the second of which received normal drinking water-and the third group consisted of normal rats that served as controls. Five/six nephrectomy produced systemic hypertension, a 50% reduction in GFR, and a 67% increase in single-nephron GFR due to elevated glomerular pressure and single-nephron plasma flow as well as proteinuria. Hypertension persisted in PPS-treated animals. Despite a similar reduction in GFR, PPS prevented the rise in single-nephron GFR, glomerular capillary hydrostatic pressure, and proteinuria. By morphometry, glomerular volume was increased by 46% and mesangial area by 94%. Fractional glomerular capillary area decreased by 24%. PPS prevented these changes. Tubular dilatation, epithelial cell atrophy, and increased interstitial area were largely prevented by PPS, as was the interstitial inflammatory infiltrate. These results suggest that the renal protection conferred by PPS was mediated both by prevention of glomerular hypertension as well as suppression of the inflammatory response. It was postulated that this was partly due to the preservation of a greater fraction of functional nephrons.
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Anticoagulantes/farmacologia , Hipertensão/patologia , Hipertensão/prevenção & controle , Glomérulos Renais/efeitos dos fármacos , Nefrectomia/métodos , Poliéster Sulfúrico de Pentosana/farmacologia , Animais , Pressão Sanguínea , Hemodinâmica/efeitos dos fármacos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Rim/patologia , Glomérulos Renais/patologia , Masculino , Proteinúria/urina , Ratos , Ratos WistarRESUMO
Antecedentes: el linfoma gástrico se ha considerado tradicionalmente una neoplasia rara que constituye del 1 a 5 por ciento de los tumores malignos del estómago. En dos estudios de 1960 y 1966 realizados en nuestro país encontró que sólo 1.9 y 1 por ciento de las neoplasias gástricas correspondían a linfoma. Sin embargo, algunos estudios realizados en Estados Unidos y algunos países europeos, en las últimas décadas, han revelado incremento en la frecuencia de esta neoplasia. Una revisión realizada en dos centros de concentración de la Ciudad de México (Instituto Nacional de la Nutrición e Instituto Nacional de Cancerología) revelaron incremento notable en la frecuencia del linfoma gástrico (9.3 y 10.3 por ciento, respectivamente) en años recientes. Objetivo: confirmar el incremento del linfoma gástrico en nuestra población y definir si incluye otros centros hospitalarios de la Ciudad de México que atienden poblaciones distintas a las de los centros de concentración. Material y método: se seleccionaron seis centros hospitalarios de la Ciudad de México incluyendo dos centros de concentración (Instituto Nacional de la Nutrición e Instituto Nacional de Cancerología), dos hospitales generales donde acuden pacientes con alto nivel socioeconómico (Hospital Español y Hospital Inglés) y dos hospitales generales donde acuden pacientes con bajos ingresos económicos (Hospital Juárez y Hospital General de México). En cada uno de ellos se anotaron los casos de linfoma gástrico diagnosticados en los últimos cinco años. Con fines comparativos se anotaron en el mismo periodo, el número de adenocarcinomas gástricos. Otras neoplasias malignas del estómago fueron excluidas del estudio porque conformaban un grupo muy heterogéneo y representaban una proporción mínima de los tumores gástricos malignos. Resultados: se obtuvieron en total 879 neoplasias gástricas malignas. El porcentaje de linfoma gástrico por institución en orden descendiente fue: Hospital Español 25.4 por ciento, Instituto Nacional de la Nutrición 13.7 por ciento, Hospital Inglés 11.5 por ciento, Hospital General de México 8.5 por ciento, Instituto Nacional de Cancerología 6 por ciento y Hospital Juárez 6 por ciento. La frecuencia general en promedio, considerando los seis hospitales fue de 9.1 por ciento