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BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disorder. When SLE occurs in individuals under the age of 18, it is referred to as childhood-onset SLE (cSLE). Currently, there is a dearth of bibliometric research pertaining to cSLE. METHOD: Relevant studies in the field of cSLE from 2000 to 2022 were screened from the Web of Science Core Collection (WoSCC). CiteSpace and VOSviewer software were used to visualize the annual publications, countries, institutions, authors, journals, keywords, and references, after which the authors conducted the scientific analysis. RESULTS: A total of 2857 articles were included in this study, and the number of articles published in the past 20 years showed an overall upwards trend. The most prolific countries are the United States, China, and Brazil; however, the United States, Canada, and the United Kingdom are clearly superior in terms of literary influence, and there is more cooperation between them and their institutions. LUPUS (n = 389) contributed the most to the variance. Brunner, HI's contribution in the field of cSLE is outstanding. The words related to 'lupus nephritis' and 'antibodies' are important words reflected in the keyword network diagram. The keywords included 'evidence-based recommendation', 'validation', 'diagnosis' and 'adult' from 2019, and 'continuous bursts' to the present. CONCLUSION: This study examined the research status of cSLE patients, discussed and analysed the research hotspots and trends in this field, and provided a reference for further research in this field to promote the development of cSLE research.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Anticuerpos , Bibliometría , BrasilRESUMEN
ABSTRACT Objectives: This study aimed to examine the relationship between vertical jumping at forces of specific time phase and sprint performance in teenage sprinters. Methods: Fifteen male teenage sprinters (age: 14±2 years, height: 168±2 cm, weight: 61±1 kg) participated in the study. The subjects performed the following bilateral/unilateral jumps on a force platform: a) squat jump (SJ), b) unilateral SJ (USJ), c) 40cm drop jump (DJ), and d) 20cm unilateral DJ (UDJ). The 60m sprint test was administered on the second day. Brower split timers were positioned to record subjects' 5m, 10m, 50m and 60m split times. The variables for inclusion were vertical jump height, maximum force, and force output at 120ms in all jumps and sprint time measures. Results: The results of the Pearson Product Moment Correlation analysis showed that SJ120ms was correlated to 5m and USJ120ms was correlated to 10m. UDJ120ms showed a stronger correlation with 50m than DJ120ms. Although significant correlations using maximum force and height were observed, there were inconsistent results between bilateral and unilateral jumps. Conclusion: Our results highlighted that jumps that have similar form with certain force outputs at specific event timing could more precisely predict sprint performance in teenage sprinters. USJ120ms and UDJ120ms could better predict the acceleration (10m) and high-speed phase (50m) in sprint performance, respectively. Moreover, coaches and practitioners should be cautious when using only jump height or maximum force to predict sprint performance, since the results could be inaccurate when specific movement variables are not thoughtfully considered. Level of evidence III.
RESUMEN Objetivos: Este estudio tuvo como objetivo examinar la relación entre el salto vertical y la fuerza en tiempo específico y el desempeño del sprint en velocistas adolescentes. Métodos: Participaron en el estudio quince adolescentes varones velocistas (edades: 14 ± 2 años, estatura: 168 ± 2 cm, peso: 61 ± 1 kg). Los individuos realizaron los siguientes saltos bilaterales y unilaterales en una plataforma de fuerza: a) squat jump (SJ), b) SJ unilateral (USJ), c) drop jump (DJ) de 40 cm e d) DJ unilateral (UDJ) de 20 cm. La prueba de sprint de 60 m se realizó el segundo día. Los cronómetros en el entrenamiento fraccionado se ajustaron para registrar tiempos de 5 m, 10 m, 50 m y 60 m. Las variables que se incluyeron fueron la altura del salto vertical, la fuerza máxima y la salida de fuerza a 120 m en todos los saltos y mediciones del tiempo del sprint. Resultados: Los resultados del análisis de correlación producto-tiempo de Pearson revelaron que el SJ de 120 m estaba correlacionado con 5 m y el USJ de 120 m estaba correlacionado con 10 m. El UDJ de 120 m tuvo una mayor correlación con el DJ de 50 m que con el de 120 m. Aunque se observaron correlaciones significativas con la fuerza y la altura máximas, algunos resultados fueron inconsistentes entre los saltos bilaterales y unilaterales. Conclusiones: Nuestros resultados pusieron de manifiesto que los saltos con una forma similar a determinadas salidas de fuerza en un tiempo específico del evento pueden predecir con mayor precisión el desempeño en el sprint en adolescentes velocistas. El USJ de 120 m y el UDJ de 120 m pueden predecir mejor, respectivamente, la aceleración (10 m) y la fase de alta velocidad (50 m) en el desempeño del sprint. Además, los entrenadores y practicantes deben ser cautelosos a la hora de utilizar únicamente la altura del salto o la fuerza máxima para predecir el desempeño en el sprint, ya que los resultados pueden ser inexactos cuando no se tienen en cuenta con precisión las variables específicas del movimiento. Nivel de evidencia III.
RESUMO Objetivos: Este estudo teve como objetivo examinar a relação entre o salto vertical e a força em tempo específico e o desempenho de sprint em velocistas adolescentes. Métodos: Quinze adolescentes velocistas do sexo masculino (idade: 14 ± 2 anos, estatura: 168 ± 2 cm, peso: 61 ± 1 kg) participaram do estudo. Os indivíduos realizaram os seguintes saltos bilaterais e unilaterais em uma plataforma de força: a) squat jump (SJ), b) SJ unilateral (USJ), c) drop jump (DJ) de 40 cm e d) DJ unilateral (UDJ) de 20cm. O teste de sprint de 60 m foi realizado no segundo dia. Os cronômetros rastreadores para treinos fracionados foram posicionados para registrar os tempos fracionados de 5 m, 10 m, 50 m e 60 m. As variáveis para inclusão foram altura do salto vertical, força máxima e saída de força a 120 m em todos os saltos e medidas de tempo do sprint. Resultados: Os resultados da análise da correlação produto-tempo de Pearson mostraram que o SJ de 120 m foi correlacionado com 5 m e USJ de 120 m foi correlacionado com 10 m. O UDJ de 120 m teve correlação mais forte com DJ de 50 m do que de 120 m. Embora tenham sido observadas correlações significativas com força e altura máximas, alguns resultados foram inconsistentes entre os saltos bilaterais e unilaterais. Conclusões: Nossos resultados destacaram que os saltos com forma semelhante a certas saídas de força no tempo específico do evento podem prever com mais precisão o desempenho no sprint em adolescentes velocistas. O USJ de 120 m e o UDJ de 120 m podem prever melhor, respectivamente, a aceleração (10 m) e a fase de alta velocidade (50 m) no desempenho no sprint. Além disso, treinadores e praticantes devem ser cautelosos ao usar apenas a altura do salto ou a força máxima para prever o desempenho no sprint, uma vez que os resultados podem ser imprecisos quando variáveis específicas do movimento não forem consideradas com precisão. Nível de evidência III.
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ABSTRACT Introduction: Reducing the risk of obesity and maintaining healthy lifestyle habits and physical exercise is very important for adolescents in a crucial period of their development. Objective: Study the effect of physical training on cardiopulmonary resistance and physical fitness in obese adolescents. Methods: Fourteen overweight or obese adolescent students were selected from a school. The experiment lasted four weeks, and the experimental group received a systematic and professional physical training intervention, with two aerobic and two endurance training sessions each week. The control group did not perform any physical exercises except free activities in physical education classes. Results: After four weeks of training, the BMI index of the experimental group changed from 32.84 to 27.68, systolic blood pressure also changed from 118.14mmHg to 93.93mmHg, and diastolic blood pressure was from 69.83mmHg to 55.34mmHg. Conclusion: Elevating professional physical training in adolescents' physical education has shown to be an important attitude to reduce and prevent obesity and its comorbidities. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.
RESUMO Introdução: A redução do risco de obesidade e a manutenção de hábitos de vida saudáveis além do exercício físico são muito importantes para os adolescentes que estão em um período crucial de seu desenvolvimento. Objetivo: Estudar o efeito do treinamento físico sobre a resistência cardiopulmonar e a aptidão física em adolescentes obesos. Métodos: Catorze estudantes adolescentes obesos ou com excesso de peso foram selecionados em uma escola. A experiência teve duração de quatro semanas onde o grupo experimental recebeu uma intervenção sistemática e profissional de treinamento físico, com um total de dois treinamentos aeróbicos e dois de endurance a cada semana. O grupo de controle não realizou exercícios físicos, exceto as atividades livres nas aulas de educação física. Resultados: Após 4 semanas de treinamento, o índice de IMC do grupo experimental mudou de 32,84 para 27,68, a pressão arterial sistólica também sofreu alterações de 118,14mmHg para 93,93mmHg, e a pressão arterial diastólica foi de 69,83mmHg para 55,34mmHg. Conclusão: Elevar o treinamento físico profissional na educação física dos adolescentes mostra-se uma atitude importante para reduzir e prevenir a obesidade e suas comorbidades. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.
RESUMEN Introducción: La reducción del riesgo de obesidad y el mantenimiento de hábitos de vida saludables además del ejercicio físico son muy importantes para los adolescentes que se encuentran en un periodo crucial de su desarrollo. Objetivo: Estudiar el efecto del entrenamiento físico sobre la resistencia cardiopulmonar y la forma física en adolescentes obesos. Métodos: Se seleccionaron catorce estudiantes adolescentes con sobrepeso u obesidad en un centro escolar. El experimento duró cuatro semanas en las que el grupo experimental recibió una intervención sistemática y profesional de entrenamiento físico, con un total de dos sesiones de entrenamiento aeróbico y dos de resistencia cada semana. El grupo de control no realizó ejercicios físicos, salvo actividades libres en las clases de educación física. Resultados: Después de 4 semanas de entrenamiento, el índice de IMC del grupo experimental cambió de 32,84 a 27,68, la presión arterial sistólica también cambió de 118,14mmHg a 93,93mmHg, y la presión arterial diastólica fue de 69,83mmHg a 55,34mmHg. Conclusión: Aumentar la preparación física profesional en la educación física de los adolescentes demuestra ser una actitud importante para reducir y prevenir la obesidad y sus comorbilidades. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.
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BINGO (BAO from Integrated Neutral Gas Observations) is a unique radio telescope designed to map the intensity of neutral hydrogen distribution at cosmological distances, making the first detection of Baryon Acoustic Oscillations (BAO) in the frequency band 980 MHz - 1260 MHz, corresponding to a redshift range 0.127 < z < 0.449. BAO is one of the most powerful probes of cosmological parameters and BINGO was designed to detect the BAO signal to a level that makes it possible to put new constraints on the equation of state of dark energy. The telescope will be built in Paraíba, Brazil and consists of two \thicksim 40m mirrors, a feedhorn array of 50 horns, and no moving parts, working as a drift-scan instrument. It will cover a 15 ^{\circ} ∘ declination strip centered at \sim \delta ⼠δ =-15 ^{\circ} ∘ , mapping \sim â¼ 5400 square degrees in the sky. The BINGO consortium is led by University of São Paulo with co-leadership at National Institute for Space Research and Campina Grande Federal University (Brazil). Telescope subsystems have already been fabricated and tested, and the dish and structure fabrication are expected to start in late 2020, as well as the road and terrain preparation.
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In this study, eight natural isocoumarins (1-8) were isolated from a marine-derived Exserohilum sp. fungus. To explore their structure-activity relationship and discover potent antimalarial leads, a small library of 22 new derivatives (1a-1n, 2a, 3a-3c, 4a-4c, and 7a) were semisynthesized by varying the substituents of the aromatic ring and the aliphatic side chains. The natural compound (1) and three semisynthetic derivatives (1d, 1n, and 2a), possessing an all-cis stereochemistry, exhibited strong antiplasmodial activity with IC50 values of 1.1, 0.8, 0.4, and 2.6 µM, respectively. Mechanism studies show that 1n inhibits hemozoin polymerization and decreases the mitochondrial membrane potential but also inhibits P. falciparum DNA gyrase. 1n not only combines different mechanisms of action but also exhibits a high therapeutic index (CC50/IC50 = 675), high selectivity, and a notable drug-like profile.
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Antimaláricos/farmacología , Ascomicetos/química , Isocumarinas/farmacología , Animales , Antozoos/microbiología , Antimaláricos/síntesis química , Organismos Acuáticos/química , China , Chlorocebus aethiops , Girasa de ADN , Hemoproteínas , Isocumarinas/síntesis química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/farmacología , Células VeroRESUMEN
Multiple myeloma is the most common hematological malignancy in Gaucher disease type 1 (GD1). There is a lack of outcome data and consensus regarding screening of gammopathies. This study explores utility of screening in Porto Alegre, Brazil, and Cincinnati, Ohio. A retrospective analysis of clinical information and laboratory data from GD1 patients was performed. Over 19 years, 68 individuals with GD1 (31 males, 37 females) underwent screening, and 20 (29.4%) had abnormalities. Twelve (17.6%) had polyclonal gammopathy (mean age 24.2 years, p = .02), seven (10%) had monoclonal gammopathy of uncertain significance (MGUS; mean age 52.7 years, p = .009). One had multiple myeloma (age 61 years). Risk factors for MGUS included male gender (p = .05), p.N409S allele (p = .032). MGUS developed in six of 62 treated and two of four untreated individuals. Of those with MGUS receiving treatment, four were on enzyme replacement therapy (ERT) and one on substrate reduction therapy (SRT). Gammopathy normalized in 13 treated individuals (10 polyclonal, three MGUS) and remained abnormal in two treated individuals (two polyclonal, two MGUS). Gammopathy relapse was seen in one individual with MGUS and three with polyclonal gammopathy. This study describes screening for gammopathies and identifies risk factors in individuals with GD1.
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Enfermedad de Gaucher , Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Adulto , Brasil/epidemiología , Niño , Femenino , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos , Adulto JovenRESUMEN
ABSTRACT Purpose: Spongioplasty (mobilization and midline approximation of the two branches of the bifid dysplastic distal corpus spongiosum) can form a covering layer for the neourethra to prevent urethrocutaneous fistula in hypospadias repair surgery. However, it remains unclear whether spongioplasty affects neourethral function. The objective of this study was to compare neourethral function after hypospadias repair with and without spongioplasty. Materials and Methods: Fourteen congenital hypospadiac New Zealand male rabbits were randomly allocated into two groups, seven animals underwent Duplay hypospadias repair and spongioplasty (experimental group), while seven underwent Duplay surgery alone (control group). Functional differences between groups were assessed by comparing neourethral compliance and flow rate. Two months after surgery, in vivo neourethral compliance was assessed by measuring intraluminal pressure with a digital pressure meter of an isolated neourethral segment, following progressive distension with 1, 2, and 3mL of air. Penises were harvested for uroflowmetry test using a simple device. Results: Postoperatively, fistula developed in one and zero rabbits in the control and experimental groups, respectively. Mean pressures tended to be higher in the experimental group than in the control group (82.14 vs. 69.57, 188.43 vs. 143.26, and 244.71 vs. 186.29mmHg for 1, 2, and 3mL of air, respectively), but the difference was not statistically significant. Mean flow rates also did not significantly differ between the experimental and control groups (2.93mL/s vs. 3.31mL/s). Conclusion: In this congenital rabbit model, no obvious functional differences were found between reconstructed urethras after hypospadias repair with and without spongioplasty.
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Humanos , Animales , Masculino , Lactante , Hipospadias , Pene , Conejos , Procedimientos Quirúrgicos Urológicos Masculinos , Colgajos Quirúrgicos , Uretra , Distribución AleatoriaRESUMEN
PURPOSE: Spongioplasty (mobilization and midline approximation of the two branches of the bifid dysplastic distal corpus spongiosum) can form a covering layer for the neourethra to prevent urethrocutaneous fistula in hypospadias repair surgery. However, it remains unclear whether spongioplasty affects neourethral function. The objective of this study was to compare neourethral function after hypospadias repair with and without spongioplasty. MATERIALS AND METHODS: Fourteen congenital hypospadiac New Zealand male rabbits were randomly allocated into two groups, seven animals underwent Duplay hypospadias repair and spongioplasty (experimental group), while seven underwent Duplay surgery alone (control group). Functional differences between groups were assessed by comparing neourethral compliance and flow rate. Two months after surgery, in vivo neourethral compliance was assessed by measuring intraluminal pressure with a digital pressure meter of an isolated neourethral segment, following progressive distension with 1, 2, and 3mL of air. Penises were harvested for uroflowmetry test using a simple device. RESULTS: Postoperatively, fistula developed in one and zero rabbits in the control and experimental groups, respectively. Mean pressures tended to be higher in the experimental group than in the control group (82.14 vs. 69.57, 188.43 vs. 143.26, and 244.71 vs. 186.29mmHg for 1, 2, and 3mL of air, respectively), but the difference was not statistically significant. Mean flow rates also did not significantly differ between the experimental and control groups (2.93mL/s vs. 3.31mL/s). CONCLUSION: In this congenital rabbit model, no obvious functional differences were found between reconstructed urethras after hypospadias repair with and without spongioplasty.
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Hipospadias , Animales , Humanos , Lactante , Masculino , Pene , Conejos , Distribución Aleatoria , Colgajos Quirúrgicos , Uretra , Procedimientos Quirúrgicos Urológicos MasculinosRESUMEN
AIM: Epidemiological studies on associations between Caesarean sections (C-sections) and attention-deficit hyperactivity disorder (ADHD) have been inconsistent, and we performed a meta-analysis. METHODS: We systematically searched PubMed and Embase to December 2018 and included nine hospital-based and population registry studies published in 2011-2018. These covered a total study cohort of more than 2.5 million people in eight countries: Australia, Brazil, Denmark, Finland, Germany, Sweden, Turkey and the UK. The analysis provided summary odds ratios (ORs) and 95% confidence intervals (CI) while taking heterogeneity into account. RESULTS: We found that that C-sections were associated with a small increase in the risk of ADHD (OR 1.14, 95% CI 1.11, 1.17, I2 0%) in offspring. In subgroup analyses, the association remained for both infants born after elective C-sections (OR, 1.15, 1.11, 1.19, I2 0%) and emergency C-sections (OR, 1.13, 1.1, 1.17, I2 45.4%). However, these were only marginally significant when we pooled data from siblings from other pregnancies (OR, 1.06, 1.00-1.13, I2 0%), implying that the association was due to confounding. CONCLUSION: The statistically significant association between C-sections and ADHD in children can be partially explained by unmeasured confounding. Further research controlling for important confounders is required before firm conclusions can be drawn.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Australia , Brasil , Cesárea , Niño , Femenino , Finlandia , Alemania , Humanos , Lactante , Embarazo , Suecia , TurquíaRESUMEN
The aim of this study was to evaluate the influence of artesunate on Th1 differentiation and its anti-tumor effect on ovarian cancer. A Murine ovarian cancer model was established by ID8 cells transplantation. The expression of miR-142 and Sirt1 proteins in peripheral CD4+ T cells were quantified with qRT-PCR and western blot, respectively. Peripheral CD4+ T cells were induced for Th1 differentiation. The percentages of apoptosis of Th1/CD4+ T cells and ovarian cancer cells were analyzed by flow cytometry. The IFN-γ level was examined through enzyme-linked immunosorbent assay. Artesunate promoted miR-142 expression in peripheral CD4+ T cells and Th1 differentiation from CD4+ T cells. Artesunate promoted cell apoptosis of ovarian cancer cells by inducing Th1 differentiation. By up-regulating miR-142, artesunate suppressed Sirt1 level and promoted Th1 differentiation. Artesunate enhanced the pro-apoptotic effects of Th1 cells on ovarian cancer via the miR-142/Sirt1 pathway. Artesunate promoted Th1 differentiation from CD4+ T cells by down-regulating Sirt1 through miR-142, thereby enhancing cell apoptosis in ovarian cancer.
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Apoptosis , Artesunato/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , MicroARNs/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Células TH1/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Artesunato/uso terapéutico , Linfocitos T CD4-Positivos/citología , Diferenciación Celular , Regulación hacia Abajo , Femenino , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Neoplasias Ováricas/inmunología , Células TH1/citologíaRESUMEN
The aim of this study was to evaluate the influence of artesunate on Th1 differentiation and its anti-tumor effect on ovarian cancer. A Murine ovarian cancer model was established by ID8 cells transplantation. The expression of miR-142 and Sirt1 proteins in peripheral CD4+ T cells were quantified with qRT-PCR and western blot, respectively. Peripheral CD4+ T cells were induced for Th1 differentiation. The percentages of apoptosis of Th1/CD4+ T cells and ovarian cancer cells were analyzed by flow cytometry. The IFN-γ level was examined through enzyme-linked immunosorbent assay. Artesunate promoted miR-142 expression in peripheral CD4+ T cells and Th1 differentiation from CD4+ T cells. Artesunate promoted cell apoptosis of ovarian cancer cells by inducing Th1 differentiation. By up-regulating miR-142, artesunate suppressed Sirt1 level and promoted Th1 differentiation. Artesunate enhanced the pro-apoptotic effects of Th1 cells on ovarian cancer via the miR-142/Sirt1 pathway. Artesunate promoted Th1 differentiation from CD4+ T cells by down-regulating Sirt1 through miR-142, thereby enhancing cell apoptosis in ovarian cancer.
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Animales , Femenino , Conejos , Neoplasias Ováricas/tratamiento farmacológico , Linfocitos T CD4-Positivos/efectos de los fármacos , Apoptosis , Células TH1/efectos de los fármacos , MicroARNs/metabolismo , Artesunato/farmacología , Neoplasias Ováricas/inmunología , Linfocitos T CD4-Positivos/citología , Regulación hacia Abajo , Diferenciación Celular , Células TH1/citología , Citometría de Flujo , Artesunato/uso terapéutico , Ratones Endogámicos C57BL , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
Glucocorticoid insensitivity is an important barrier to the treatment of several inflammatory diseases, including acute lung injury (ALI). Saquinavir (SQV) is an inhibitor of the human immunodeficiency virus protease, and the therapeutic effects of SQV in ALI accompanied with glucocorticoid insensitivity have not been previously investigated. In this study, the effects of SQV on lipopolysaccharide (LPS)-mediated injury in human pulmonary microvascular endothelial cells (HPMECs), human type I alveolar epithelial cells (AT I), and alveolar macrophages were determined. In addition, the effects of SQV on an LPS-induced ALI model with or without methylprednisolone (MPS) were studied. In LPS-stimulated HPMECs, SQV treatment resulted in a decrease of high mobility group box 1 (HMGB1), phospho-NF-κB (p-NF-κB), and toll-like receptor 4 (TLR4), and an increase of VE-cadherin. Compared to MPS alone, MPS plus SQV attenuated the decrease of glucocorticoid receptor alpha (GRα) and IκBα in LPS-stimulated HPMECs. HMGB1, TLR4, and p-NF-κB expression were also lessened in LPS-stimulated alveolar macrophages with SQV treatment. In addition, SQV reduced the injury in human AT I with a decrease of HMGB1 and p-NF-κB, and with an increase of aquaporin 5 (AQP 5). SQV ameliorated the lung injury caused by LPS in rats with reductions in vascular permeability, myeloperoxidase activity (MPO) and histopathological scores, and with lowered HMGB1, TLR4, and p-NF-κB expression, but with enhanced VE-cadherin expression. By comparison, SQV plus MPS increased GRα and IκBα in lung tissues of rats with ALI. This study demonstrated that SQV prevented experimental ALI and improved glucocorticoid insensitivity by modulating the HMGB1/TLR4 pathway.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Metilprednisolona/administración & dosificación , Saquinavir/administración & dosificación , Lesión Pulmonar Aguda/inducido químicamente , Animales , Antígenos CD/efectos de los fármacos , Antígenos CD/metabolismo , Cadherinas/efectos de los fármacos , Cadherinas/metabolismo , Modelos Animales de Enfermedad , Proteína HMGB1/efectos de los fármacos , Proteína HMGB1/metabolismo , Lipopolisacáridos , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/efectos de los fármacos , Receptor Toll-Like 4/metabolismoRESUMEN
Glucocorticoid insensitivity is an important barrier to the treatment of several inflammatory diseases, including acute lung injury (ALI). Saquinavir (SQV) is an inhibitor of the human immunodeficiency virus protease, and the therapeutic effects of SQV in ALI accompanied with glucocorticoid insensitivity have not been previously investigated. In this study, the effects of SQV on lipopolysaccharide (LPS)-mediated injury in human pulmonary microvascular endothelial cells (HPMECs), human type I alveolar epithelial cells (AT I), and alveolar macrophages were determined. In addition, the effects of SQV on an LPS-induced ALI model with or without methylprednisolone (MPS) were studied. In LPS-stimulated HPMECs, SQV treatment resulted in a decrease of high mobility group box 1 (HMGB1), phospho-NF-κB (p-NF-κB), and toll-like receptor 4 (TLR4), and an increase of VE-cadherin. Compared to MPS alone, MPS plus SQV attenuated the decrease of glucocorticoid receptor alpha (GRα) and IκBα in LPS-stimulated HPMECs. HMGB1, TLR4, and p-NF-κB expression were also lessened in LPS-stimulated alveolar macrophages with SQV treatment. In addition, SQV reduced the injury in human AT I with a decrease of HMGB1 and p-NF-κB, and with an increase of aquaporin 5 (AQP 5). SQV ameliorated the lung injury caused by LPS in rats with reductions in vascular permeability, myeloperoxidase activity (MPO) and histopathological scores, and with lowered HMGB1, TLR4, and p-NF-κB expression, but with enhanced VE-cadherin expression. By comparison, SQV plus MPS increased GRα and IκBα in lung tissues of rats with ALI. This study demonstrated that SQV prevented experimental ALI and improved glucocorticoid insensitivity by modulating the HMGB1/TLR4 pathway.
Asunto(s)
Animales , Masculino , Ratas , Metilprednisolona/administración & dosificación , Saquinavir/administración & dosificación , Lesión Pulmonar Aguda/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Antígenos CD/efectos de los fármacos , Antígenos CD/metabolismo , Cadherinas/efectos de los fármacos , Cadherinas/metabolismo , Lipopolisacáridos , Ratas Sprague-Dawley , Proteína HMGB1/efectos de los fármacos , Proteína HMGB1/metabolismo , Modelos Animales de Enfermedad , Receptor Toll-Like 4/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Lesión Pulmonar Aguda/inducido químicamenteRESUMEN
BACKGROUND: Insulin degrading enzyme (IDE) is implicated in the regulation of amyloid beta (Abeta) steady-state levels in the brain, and its deficient expression and/or activity may be a risk factor in sporadic Alzheimer's disease (AD). Although IDE sub-cellular localization has been well studied, the compartments relevant to Abeta degradation remain to be determined. RESULTS: Our results of live immunofluorescence, immuno gold electron-microscopy and gradient fractionation concurred to the demonstration that endogenous IDE from brain tissues and cell cultures is, in addition to its other localizations, a detergent-resistant membrane (DRM)-associated metallopeptidase. Our pulse chase experiments were in accordance with the existence of two pools of IDE: the cytosolic one with a longer half-life and the membrane-IDE with a faster turn-over. DRMs-associated IDE co-localized with Abeta and its distribution (DRMs vs. non-DRMs) and activity was sensitive to manipulation of lipid composition in vitro and in vivo. When IDE was mis-located from DRMs by treating cells with methyl-beta-cyclodextrin (MbetaCD), endogenous Abeta accumulated in the extracellular space and exogenous Abeta proteolysis was impaired. We detected a reduced amount of IDE in DRMs of membranes isolated from mice brain with endogenous reduced levels of cholesterol (Chol) due to targeted deletion of one seladin-1 allele. We confirmed that a moderate shift of IDE from DRMs induced a substantial decrement on IDE-mediated insulin and Abeta degradation in vitro. CONCLUSION: Our results support the notion that optimal substrate degradation by IDE may require its association with organized-DRMs. Alternatively, DRMs but not other plasma membrane regions, may act as platforms where Abeta accumulates, due to its hydrophobic properties, reaching local concentration close to its Km for IDE facilitating its clearance. Structural integrity of DRMs may also be required to tightly retain insulin receptor and IDE for insulin proteolysis. The concept that mis-location of Abeta degrading proteases away from DRMs may impair the physiological turn-over of Abeta in vivo deserves further investigation in light of therapeutic strategies based on enhancing Abeta proteolysis in which DRM protease-targeting may need to be taken into account.