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Ubiquitin-proteasome system (UPS) plays an important role in neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The discovery of UPS activators for anti-neurodegenerative diseases is becoming increasingly important. In this study, we aimed to identify potential UPS activators using the high-throughput screening method with the high-content fluorescence imaging system and validate the neuroprotective effect in the cell models of AD. At first, stable YFP-CL1 HT22 cells were successfully constructed by transfecting the YFP-CL1 plasmid into HT22 cells, together with G418 screening. The degradation activity of the test compounds via UPS was monitored by detecting the YFP fluorescence intensity reflected by the ubiquitin-proteasome degradation signal CL1. By employing the high-content fluorescence imaging system, together with stable YFP-CL1 HT22 cells, the UPS activators were successfully screened from our established TCM library. The representative images were captured and analyzed, and quantification of the YFP fluorescence intensity was performed by flow cytometry. Then, the neuroprotective effect of the UPS activators was investigated in pEGFP-N1-APP (APP), pRK5-EGFP-Tau P301L (Tau P301L), or pRK5-EGFP-Tau (Tau) transiently transfected HT22 cells using fluorescence imaging, flow cytometry, and Western blot. In conclusion, our study established a high-content fluorescence imaging system coupled with stable YFP-CL1 HT22 cells for the high-throughput screening of the UPS activators. Three compounds, namely salvianolic acid A (SAA), salvianolic acid B (SAB), and ellagic acid (EA), were identified to significantly decrease YFP fluorescence intensity, which suggested that these three compounds are UPS activators. The identified UPS activators were demonstrated to clear AD-related proteins, including APP, Tau, and Tau P301L. Therefore, these findings provide a novel insight into the discovery and development of anti-AD drugs.
Subject(s)
Humans , Alzheimer Disease/drug therapy , Neuroprotective Agents , Optical Imaging , Proteasome Endopeptidase Complex , UbiquitinABSTRACT
Introdução: No contexto do Sistema Único de Saúde, o conceito da prevenção quaternária adentra timidamente os níveis de atenção à saúde, no entanto, sofre expansão significativa no âmbito da atenção primária à saúde. Objetivo: Identificar por meio da sistematização de evidências científicas, as contribuições técnicas e socioculturais da prevenção quaternária no âmbito da atenção primária à saúde no Brasil. Métodos: Trata-se de uma revisão integrativa de estudos presentes nas bases de dados científicas da Scientific Electronic Library Online, Biblioteca Virtual em Saúde, biblioteca virtual da Comissão de Aperfeiçoamento de Pessoal do Nível Superior e MEDLINE via PubMed com a utilização dos descritores "prevenção quaternária" e "atenção primária à saúde", em inglês e português. Resultados: O corpus de análise foi composto por 22 artigos, sendo que a produção científica sobre o tema se deu de forma mais intensa a partir do ano de 2015 e, em sua maioria, possuíam como abordagem metodológica ensaios teóricos. Dentre as contribuições técnicas destacaram-se a introdução do ensino da prevenção quaternária de modo continuado aos graduandos e profissionais; a construção de protocolos e documentos de amparo profissional; a utilização de modelos explicativos dinâmicos na socialização do quadro clínico; a conduta profissional com os usuários e as contribuições socioculturais envolvendo mudanças na percepção profissional e comunitária sobre o fenômeno saúde-doença, assim como o incentivo a práticas de desmedicalização sociocultural em relação à dor, incapacidade, desconforto, envelhecimento, nascimento e morte. Conclusão: Apesar do reconhecimento das potencialidades da prevenção quaternária, faz-se necessário fortalecer estratégias que possibilitem o desenvolvimento de políticas públicas para fomentar e gerenciar alianças estratégicas com tomadores de decisão, profissionais de saúde e cidadãos, para fomentar a redução de diagnósticos e tratamentos excessivos, contribuindo com a qualidade do cuidado.
Introduction: In the context of the Unified Health System, the concept of quaternary prevention shyly enters the levels of health care, however, undergoes significant expansion in the scope of primary health care. Objective: To identify, through the systematization of scientific evidence, the technical and socio-cultural contributions of quaternary prevention within the scope of primary health care in Brazil. Methods: This is an integrative review of studies present in the scientific databases of the Scientific Electronic Library Online, Regional Portal of the Virtual Health Library of the Latin American and Caribbean Center on Health Sciences Information of the Pan American Health Organization, virtual library of the Higher Education Personnel Improvement Commission, and MEDLINE through PubMed using the descriptors "quaternary prevention" and "primary health care", in English and Portuguese. Results: The corpus of analysis consisted of 22 articles, and the scientific production on the topic took place more intensively from the year 2015 and, for the most part, had theoretical essays as methodological approach. Among the technical contributions, we highlight the introduction of teaching on quaternary prevention in a continuous way to undergraduates and professionals; the construction of protocols and documents of professional support; the use of dynamic explanatory models in the socialization of the clinical picture and professional conduct with users and socio-cultural contributions involve changes in the professional and community perception about the phenomenon of illness and health conception, as well as the incentive to practices of socio-cultural demedicalization in relation to pain, disability, discomfort, aging, birth, and death. Conclusion: Despite the recognition of the potential of quaternary prevention, it is necessary to strengthen strategies that enable the development of public policies to foster and manage strategic alliances with decision makers, health professionals and citizens, to promote the reduction of excessive diagnoses and treatments, contributing to the quality of care.
Introducción: En el contexto del Sistema Único de Salud, el concepto de prevención cuaternaria entra tímidamente en los niveles de atención de salud, sin embargo, experimenta una expansión significativa en el alcance de la Atención Primaria de Salud. Objetivo: Identificar, a través de la sistematización de evidencia científica, las contribuciones técnicas y socioculturales de la prevención cuaternaria en el ámbito de la Atención Primaria de Salud en Brasil. Métodos: Esta es una revisión integradora de estudios presentes en las bases de datos científicas de la Biblioteca Electrónica Científica en línea, Portal Regional de la Biblioteca Virtual en Salud del Centro Latinoamericano y del Caribe de Información en Ciencias de la Salud de la Organización Panamericana de la Salud, biblioteca virtual de la Comisión de Mejoramiento del Personal de Educación Superior y MEDLINE a través de PubMed utilizando los descriptores de prevención cuaternaria y atención primaria de salud, en inglés y portugués. Resultados: El corpus de análisis estuvo conformado por 22 artículos, siendo la producción científica sobre el tema más intensiva desde 2015 y, en su mayor parte, tuvo ensayos teóricos como abordaje metodológico. Entre los aportes técnicos, destacamos la implantación de la docencia en prevención cuaternaria de forma continua a estudiantes de pregrado y profesionales; construcción de protocolos y documentos de apoyo profesional, uso de modelos explicativos dinámicos en la socialización del cuadro clínico y conducta profesional con los usuarios y los aportes socioculturales implican cambios en la percepción profesional y comunitaria sobre el fenómeno de la enfermedad y la concepción de la salud, así como el incentivo a prácticas de desmedicalización sociocultural en relación al dolor, discapacidad, malestar, envejecimiento, nacimiento y muerte. Conclusión: A pesar del reconocimiento del potencial de la prevención cuaternaria, es necesario fortalecer estrategias que permitan el desarrollo de políticas públicas para fomentar y gestionar alianzas estratégicas con los tomadores de decisiones, profesionales de la salud y ciudadanos, para promover la reducción de diagnósticos y tratamientos excesivos, contribuyendo a la calidad de la atención.
Subject(s)
Primary Health Care , Unified Health System , Family Practice , Medical Overuse , Quaternary PreventionABSTRACT
Objective: For the purpose of finding new bioactive agents from ethnic medicines, the chemical study on Dai Medicine Cassia alata was carried out. Methods: The chemical constituents from the twigs of C. alata were isolated by column chromatographic methods of silica gel, MCI-Gel resin, Sephadex LH-20, and HPLC. The structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. The cytotoxicity of this compound for NB-4, A-549, SHSY5Y, PC-3, and MCF-7 cells line was also evaluated by using the MTT method. Results: Four 2-arylbenzofuran compounds were isolated from this plant and identified as 7- methoxy-2-(4-methoxyphenyl)-3,5-dimethylbenzofuran (1), moracin N (2), 2-(2'-methoxy-4'-hydroxy-aryl)-3-methy-6-hydroxybenzofuran (3), and moracin P (4). Conclusion: Compound 1 is a new compound named as 7-methoxy-2-(4-methoxyphenyl)-3,5-dimethylbenzofuran. Compound 1 also displays the high cytotoxicity to tested cancer cell-line.
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This study was aimed to investigate the effect of baicalin on the proportion of Th22 cells and the concentration of IL-22 bothin vivo andin vitro, in order to explore the immune mechanism of baicalin on inflammatory bowel disease mice model. The 3.5% dextran sodium sulfate (DSS) was used on C57BL/6 mice for the establishment of colitis mice model. Mice were randomly divided into the blank control group, model group, and baicalin group. Flow cytometry and ELISA were used in the detection of the proportion of Th22 cells and concentration of IL-22 in peripheral blood serum, respectively. The spleen lymphocytes of mice were isolated and cultured by baicalin medium (0, 10, 20, 40μM) for 48 h. Flow cytometry was used in the detection of the proportion of Th22 cells. The results showed that baicalin reduced the proportion of Th22 cells and the expression of IL-22 bothin vivo andin vitro experiments. It was concluded that baicalin can inhibit Th22 cell differentiation and expression of IL-22in vitro and DSS-induced colitis mice. It indicated that baicalin had a good treatment potential in Th22 cell-mediated inflammatory diseases.
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