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Efecto de cucurbita ficifolia Bouché sobre marcadores inflamatorios y PPARs en macrófagos y adipocitos en co-cultivo
Get PDFLa obesidad es una de las enfermedades crónico-degenerativas más comunes a nivel mundial y nacional. Es el principal factor de riesgo para desarrollar padecimientos como la Diabetes Tipo 2 (DT2), hipertensión, complicaciones cardiovasculares e incluso algunos tipos de cáncer. Su etiología es multifactorial, entre los factores que caracterizan su desarrollo se encuentran el estilo de vida sedentario y una mala alimentación, así como factores genéticos y ambientales. Se caracteriza por una acumulación excesiva de tejido adiposo, principalmente en la zona central del cuerpo. Así mismo, la obesidad desarrolla estados de inflamación crónica de bajo grado, en donde la participación de los macrófagos es crucial para el mantenimiento de dicho estadio de inflamación. La inflamación crónica de bajo grado se caracteriza por la secreción continua de mediadores inflamatorios, principalmente citocinas, así como la infiltración de macrófagos al tejido adiposo, lo que convierte a dicho tejido como una fuente importante de generación de citocinas inflamatorias. El estado de inflamación crónico de bajo grado se ha asociado con el desarrollo de resistencia a la insulina, así como de complicaciones vasculares. En la actualidad existe un gran número de fármacos utilizados para tratar la obesidad y patologías asociadas a ella. Sin embargo, dicha terapéutica tiene como objetivos principales; disminuir la absorción de ácidos grasos (Orlistat), favorecer la oxidación de los ácidos grasos y disminuir la dislipidemia (fibratos) o disminuir los niveles de glucosa (antidiabéticos). Dejando de lado el tratar de restablecer la condición inflamatoria que caracteriza a la enfermedad. En México, la población hace uso de la medicina tradicional como medio alternativo para su tratamiento. Dentro de las especies ampliamente estudias, con propiedades antidiabéticas y antiinflamatorias se encuentra Cucurbita ficifolia. El objetivo de éste trabajo fue evaluar el efecto de un extracto estandarizado de Cucurbita ficifolia, sobre la expresión de RNAs mensajeros de receptores activados por proliferadores de peroxisomas (PPARs), transportadores involucrados en el metabolismo de glucosa y ácidos grasos (GLUT-4, FATP-1), citocinas y liberación de las mismas, en adipocitos 3T3-L1 y macrófagos RAW 264.7 sometidos a un co-cultivo. En este estudio logramos observar que el extracto de Cucurbita ficifolia, produce un incremento en la expresión de GLUT-4 y un descenso en FATP-1, en adipocitos sometidos a co-cultivo por intercambio de medio de cultivo, y la liberación de TNF-α e IL-6 incrementa, mientras que la liberación de IL-1β disminuye. Por el contrario, cuando los macrófagos son sometidos a co-cultivo por intercambio de medio de adipocitos tratados con Cucurbita ficifolia, TNF-α, IL-6 e IL-10 disminuyen su liberación a la vez que disminuye la expresión de TLR-4. De manera similar, cuando el co-cultivo de las líneas celulares fue simultáneo, la liberación general de TNF-α, IL-6 e IL-10 disminuyó y se dio un incremento en la expresión de PPARγ por parte de los adipocitos. El extracto fue estandarizado con base en su contenido de salicina y fue utilizado a una concentración de 10 µg/ml. Los resultados derivados de ésta investigación permiten concluir que la relación tan estrecha que existe entre el adipocito y el macrófago, influye sobre el patrón de expresión y liberación de citocinas. Cucurbita ficifolia genera efectos directos en ambos tipos celulares, ya que modifica el patrón de secreción de citocinas como TNF-α e IL6, las cuales son producidas por los dos tipos celulares. Es necesario continuar con la investigación de Cucurbita ficifolia, en particular de moléculas identificadas con potencial farmacológico como la salicina, la cual puede ser la responsable de su actividad antinflamatoria, debido a su naturaleza química.Obesity is becoming one of the most common chronic-degenerative diseases worldwide. It is the number one risk factor to develop pathologies such as Type 2 Diabetes, high blood pressure, cardiovascular diseases and even some types of cancer. It is a multifactorial condition commonly caused by a combination of excessive food intake, lack of physical activity, and genetic susceptibility (Yazdi, Clee et al. 2015). It Is defined as the accumulation of excess body fat to the extent that it results in other health complications, reducing life expectancy (Bahreini, Noor et al., 2013). Nowadays, there are several pharmacological treatments for obesity related pathologies, however, such therapeutics are aimed towards fatty acids absorption, oxidation, and controlling their blood levels and decreasing glycaemia, leaving aside the restoration of the inflammatory condition that characterizes the disease. In Mexico, the population uses traditional plants as an alternative treatment. Cucurbita ficifolia is an example of the species widely used and studied, it has shown anti-diabetical and anti-inflammatory properties. The aim of this study was to evaluate the effect of a standardized Cucurbita ficifolia extract, over expression of peroxisome proliferators activated receptors (PPARs), metabolic associated genes (GLUT-4, FATP-1), citokines expression and secretion (TNF-α, IL-6, IL-10, IL-1β) in 3T3-L1 adipocytes and RAW 264.7 macrophages, under co-cultured conditions. Extract was standardized under its salicin content and was applied at a 10 µg per ml to the cells. C. ficifolia extract produced an increased GLUT-4 expression, and decreased FATP-1 in adipocytes with treated macrophages conditioned media exchange, as well as an increased TNF-α and IL-6, and decreased IL-1β secretion. Contrary to this, when macrophages were treated with adipocyte conditioned media (treated with C. ficifolia), TNF-α, IL-6 and IL-10 secretion declines, while TLR-4 expression is lowered. When both cell lines where co-cultured simultaneously, the overall release of TNF-α IL6 and IL-10 decreased, while adipocyte expression of PPARγ increased. These results allow us to conclude that a close relationship between adipocytes and macrophages, influence the gene expression pattern and cytokine release. C. ficifolia generates direct effects in both cell types, as it modifies secretion patterns such as those given for TNF-α and IL-6, which are produced by the two cell types. It is still necessary to continue the research on C. ficifolia, to identify molecules with pharmacological potential, such as salicin, which may be responsible for its biological activity
Estudio químico biodirigido de Cucurbita ficifolia Bouché en modelos hipoglucémicos y antihiperglucémicos: análisis in vivo, in vitro e in silico
Get PDFIntroducción La diabetes mellitus tiene como característica principal un estado sostenido de hiperglucemia, resultante de una deficiente secreción de insulina por parte de las células β-pancreáticas, resistencia a su acción en tejidos diana, o ambas. Se trata de un padecimiento complejo que involucra diversas alteraciones metabólicas. Cucurbita ficifolia Bouché es una especie vegetal utilizada comúnmente como antidiabético dentro de la medicina tradicional mexicana. En estudios previos ha mostrado efectos hipoglucemiante, antioxidante y antinflamatorio, entre otros. A pesar de ello, aún no se cuenta con un análisis fitoquímico biodirigido que permita conocer los compuestos bioactivos y responsables de estas acciones, en particular de la acción hipoglucemiante. Dentro de los puntos clave en la regulación de la glucosa, existen tejidos clave como el músculo esquelético, el tejido adiposo, el páncreas y el hígado, cada uno de ellos involucrado en actividades como la oxidación, el almacenamiento de energía y la producción de insulina. Por ello, las células que conforman estos tejidos representan modelos biológicos útiles para llevar a cabo un fraccionamiento biodirigido a partir del extracto activo de C. ficifolia. Material y métodos Se obtuvieron tres preparaciones a partir de C. ficifolia utilizando disolventes de distinta polaridad: extracto acetónico, extracto acuoso y bipartición del extracto acuoso en acetato de etilo denominada fracción de AcOEt. Se evaluó su efecto hipoglucémico y antihiperglucémico in vivo para seleccionar el extracto o fracción más activa y realizar su fraccionamiento por cromatografía. Las fracciones y subfracciones se sometieron a bioensayos in vitro: en células pancreáticas RINm5F para evaluar su efecto sobre la secreción de insulina y en miocitos C2C12 para evaluar la expresión del ARNm de GLUT-4. Ambos modelos fueron empleados como modelos de monitoreo para llevar a cabo una separación guiada, así como la purificación e identificación de los compuestos presentes en la fracción activa. Los compuestos identificados fueron también evaluados en estos mismos ensayos biológicos, así como en células HepG2 para evaluar su efecto sobre la acumulación de glucógeno y en un modelo in vivo usando ratones diabéticos. Además, con los compuestos identificados se realizó un análisis de acoplamiento molecular sobre los receptores PPARγ y GPR40. Resultados La fracción de acetato de etilo derivada del extracto acuoso mostró efecto hipoglucemiante en el modelo agudo y un contundente efecto antihiperglucemiante en la prueba de tolerancia a la glucosa oral, por lo que se procedió a la separación química de sus componentes. Las fracciones y subfracciones obtenidas se evaluaron en modelos in vivo e in vitro y a partir de ellas se logró identificar los compuestos β-sitosterol y ácido 4- hidroxibenzoico, que mostraron acción dual sobre la expresión de GLUT-4 y secreción de insulina, así como incremento en la expresión de adiponectina y PPARγ, además de incremento en la deposición de glucógeno en células hepáticas. β-sitosterol mostró efecto antihiperglucémico, mientras que el ácido 4- hidroxibenzoico exhibió mayor efecto hipoglucémico en ratones diabéticos. En los estudios in silico, ambos compuestos mostraron potencial como agonistas parciales de receptores GPR40 y PPARγ. Conclusión A través de un fraccionamiento químico guiado por ensayos biológicos se identificaron los compuestos β-sitosterol y ácido 4-hidroxibenzoico como los compuestos mayoritarios de la fracción de acetato de etilo de C. ficifolia, los cuales mostraron acción secretagoga de insulina y acción agonista sobre PPARγ, además de efecto sobre la deposición de glucógeno. Estos compuestos podrían explicar, en parte, los efectos hipoglucemiante y antihiperglucémico de C. ficifolia, representando dos entidades químicas significantes para el diseño de nuevos fármacos con múltiples blancos moleculares con utilidad en el tratamiento de enfermedades metabólicas.Introduction Diabetes mellitus comprises a wide range of metabolic diseases and is mainly characterized by a chronic state of hyperglycemia, resulting from defects on the secretion and action of the insulin in peripheral tissues. Chronic hyperglycemia is associated with disfunction and damage on the long term, such as organic failure, especially eyes, kidneys, nerves, heart, and vascular system. Cucurbita ficifolia Bouché is a plant commonly used in traditional Mexican medicine to treat diabetes mellitus. In previous studies it has shown diverse effects such as hypoglycemic, antioxidant, and antinflammatory. However, there is still no phytochemical analysis that will allow the identification of bioactive compounds responsible for their hypoglycaemic effect. Among the key points in glucose regulation are the cells of the skeletal muscle, adipose tissue, pancreas and liver, which are involved in activities such as oxidation, energy storage, and insulin production. These cells can serve as biological models for performing a chemical fractionation guided by bioessay of the active extract of C. ficifolia. Material and methods Three extracts of different polarity of C. ficifolia were obtained: acetonic extract, aqueous extract, and a bipartition of the aqueous extract in ethyl acetate (AcOEt fraction). The hypoglycemic and antihyperglycemic effects of these extracts were evaluated in models in vivo to select the most active extract or fraction and carry out a chromatographic fractionation. The fractions and subfractions were subjected to bioassays in RINm5F pancreatic cells to evaluate their effect on insulin secretion, as well as in C2C12 myoblasts to evaluate the expression of GLUT-4 mRNA. Both were used as monitoring models to perform a guided separation, as well as the purification and identification of chemical compounds. The identified compounds were also evaluated in these in vitro models, and in HepG2 cells to evaluate effect on glycogen accumulation, as well as in diabetic mice. In addition, with the identified compounds, a molecular docking analysis on PPARγ and GPR40 was conducted. Results Aqueous extract exhibited hypoglycemic effect in an acute In vivo model. Ethyl acetate fraction derived from aqueous extract showed a robust antihyperglycemic effect in oral glucose tolerance test (OGTT) and was further fractionated. Chemical separation of fractions was guided by biological In vitro activity over GLUT-4 expression in C2C12 muscular cells, and insulin secretion in RINm5F pancreatic cells. The fractions and subfractions that increased expression of glucose transporter GLUT-4, and insulin secretion, were further separated and analyzed. βsitosterol and 4-hydroxybenzoic acid were identified as active compounds of ethyl acetate fraction and active subfractions. Isolated compounds were evaluated In vitro and found to increase both insulin secretion and GLUT4 mRNA expression. Additionally, compounds increased glycogen synthesis in HepG2 cells, β-sitosterol exhibited an antihyperglycemic effect, on oral glucose tolerance test in diabetic mice, while 4-hydroxybenzoic acid had a hypoglycemic effect in acute In vivo model. Molecular docking revealed potential as partial agonists over GPR40 and PPARγ receptors. Conclusion Through a method guided by biological assays, β-sitosterol and 4-hydroxybenzoic acid were identified as majoritarian compounds in an ethyl acetate fraction of C. ficifolia, with insulin secretagogue action and agonist action on PPARγ, showing an effect on glycogen deposition. These compounds could be associated with the hypoglycemic and antihyperglycemic effects exerted by C. ficifolia. Both compounds represent important chemical entities for the design of new drugs with multiple molecular targets and utility in the treatment of metabolic diseases
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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