Retraction notice to "Curcumin restores Nrf2 levels and prevents quinolinic acid-induced neurotoxicity " [JNB 24 (2013) 14-24].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief as it contains inappropriately manipulated images in Figure 7B. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter, and apologies are offered to the readers of the journal that this problem was not detected during the submission process.

A two-step synthetic strategy to obtain a water-soluble derivative of curcumin with improved antioxidant capacity and in vitro cytotoxicity in C6 glioma cells.

A novel water-soluble derivative of curcumin (Cur-[G-2]-OH) was designed and synthesized from accessible raw materials in only two steps with an overall yield of 80%. The modification of curcumin phenol groups with second-generation polyester dendrons (dendronization) as a strategy to achieve an optimal hydrophilic/hydrophobic balance allows the complete water solubilization of the new curcumin derivative (5mg/ml) at room temperature. The therapeutic potential of Cur-[G-2]-OH was investigated in terms of antioxidant capacity, intracellular uptake and cytotoxicity in both rat glioblastoma cells and normal human dermal fibroblasts. Although the phenolic groups of curcumin were locked by dendronization, Cur-[G-2]-OH exhibited antioxidant capacity in water that was even higher than curcumin in dimethylsulfoxide (DMSO). This compound showed a steady cellular uptake contrasted with curcumin, which has a saturation capture at high concentrations. Combined with improved stability, this property seems to allow the intracellular accumulation of Cur-[G-2]-OH. Furthermore, the new compound exhibited increased cytotoxicity in rat C6 glioma cells in a time- and concentration-dependent manner, whereas in normal human fibroblasts, its IC50 value was >600µM versus the IC50 of curcumin found between 100 and 200µM. Surprisingly, Cur-[G-2]-OH drives cell death of C6 cells by a different mechanism of apoptosis triggered by curcumin. Together, these results suggest that curcumin dendronization could promote molecular and cellular mechanisms that are different from those induced by curcumin, presumably due to structural factors and not only for improved water solubility.

Grupos interactivos en aula y el incremento de los resultados de aprendizaje en lenguaje en un colegio vulnerable / Grupos interativos em sala de aula e o progresso dos resultados de aprendizagem em linguagem em uma escola em situação de vulnerabilidade / Interactive groups in the classroom and the language learning progress in a school in vulnerability situation

RESUMEN: Este artículo presenta los resultados de un estudio realizado entre los años 2013 y 2014 en un colegio vulnerable2 en Los Ángeles, Chile. Ese estudio consistió en la incorporación de grupos interactivos en aula en primero básico3 en Lenguaje. El objetivo fue determinar el incremento de los resultados de aprendizaje en dicha área. Se utilizó un enfoque cuantitativo, con diseño preexperimental y aplicación de CL-PT4 en el nivel señalado, antes y después de la intervención. El trabajo, además, consideró la incorporación en aula de colaboradores de aprendizaje: apoderados, alumnos de cursos superiores del mismo colegio, alumnas de pregrado y docentes de la Universidad. Los grupos interactivos involucran un cambio de paradigma que conlleva un fuerte compromiso social. Los resultados indican que se produjo un incremento significativo entre el pretest y postest (CL-PT), lo que implicó una mejora en el desarrollo del lenguaje.

RESUMO: Este artigo apresenta os resultados de um estudo realizado entre 2013 e 2014 em um colégio em situação de vulnerabilidade5 em Los Ángeles, Chile. Esse estudo consistiu na incorporação de grupos interativos em sala de aula no primeiro ano básico6 em Linguagem. O objetivo foi delinear o progresso dos resultados de aprendizagem nessa área. Utilizou-se um enfoque quantitativo, com uma configuração pré-experimental e aplicação de CL-PT7 no nível escolar já mencionado, antes e depois da intervenção. O trabalho, além disso, considerou a incorporação em sala de aula de colaboradores de aprendizagem: pais ou responsáveis pelos alunos; alunos de anos posteriores do mesmo colégio; alunas de graduação; e docentes da Universidade. Os grupos interativos envolvem uma mudança de paradigma que implica um forte compromisso social. Os resultados indicam que se produziu um progresso significativo entre o pré-teste e o pós-teste (CL-PT), o que acarretou uma melhora no desenvolvimento da linguagem.

This article presents the results of a study performed during the 2013 to 2014 period in a "vulnerable" school in Los Angeles, Chile. The study has consisted of the incorporation of interactive groups in first grade language classes. The aim was to determine increased learning outcomes in this area. A quantitative approach was used with a pre-experimental design and the application of reading comprehension and text production tests in the mentioned grade, before and after the intervention. Furthermore, this study also considered the incorporation of learning collaborators into the classroom: parents or guardians, students in higher grades in the same school, undergraduate students, and university professors. The interactive groups involve a paradigm change that leads to a strong social commitment. The results indicate that a significant increase was produced between the pre and post test, which led to an improvement in language learning.

The MLN4924 inhibitor exerts a neuroprotective effect against oxidative stress injury via Nrf2 protein accumulation.

It was explored the cytoprotective and antioxidant effect of MLN4924, a specific inhibitor of Nedd8-activating enzyme (NAE), against hydrogen peroxide (H2O2)-induced damage in cerebellar granule neurons (CGNs). Primary cultures of CGNs were exposed to H2O2 after preincubation with MLN4924. The compounds were removed, and CGNs were incubated in culture medium for 24h in order to determine cell viability by 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyl-tetrazolium bromide (MTT) and fluorescein diacetate (FDA) assays. It was demonstrated that MLN4924 remarkably attenuated H2O2-induced cell damage. Meanwhile reactive oxygen species (ROS) production was evaluated with the fluorescent probe dihydroethidium (DHE). Interestingly H2O2-induced ROS production was inhibited by pretreatment with MLN4924. MLN4924 treatment in CGNs resulted in nuclear factor E2-related factor 2 (Nrf2) protein accumulation. Intriguingly this effect was observed in the cytosolic and nuclear compartments of the CGNs. The cytoprotective effect of MLN4924 was associated with its ability to diminish ROS production induced by H2O2 and the accumulation of Nrf2 protein levels in the cytoplasm and nucleus of the CGNs.

Cullin 3 as a novel target in diverse pathologies.

Recent evidence suggests that the malfunctioning disposal system of cell protein called ubiquitin-proteasome system (UPS) plays an important role in the development of disorders, including cancer and neurodegenerative diseases. Accumulating evidence suggests that the abnormal regulation of the E3 ubiquitin ligases, essential components of the UPS, contributes to uncontrolled proliferation, genomic instability and cancer, since these ligases and their substrates are involved in the regulation of cell cycle progression, gene transcription, signal transduction, DNA replication and others. Through selective degradation of specific substrates, E3 ligases regulate different biological processes. Cullins are a family of proteins that confer substrate specificity to multimeric complex of E3 ligases acting as scaffold proteins. So far, seven members of the cullin family of proteins have been identified. Interestingly, the data generated by several groups indicate that cullin 3 (Cul3) has begun to emerge as a protein involved in the etiopathology of multiple diseases. In this paper we examine the latest advances in basic research on the biology of Cul3 and how it could help to direct drug discovery efforts on this target.

RETRACTED: Curcumin restores Nrf2 levels and prevents quinolinic acid-induced neurotoxicity.

Neurological diseases comprise a group of heterogeneous disorders characterized by progressive brain dysfunction and cell death. In the next years, these diseases are expected to constitute a world-wide health problem. Because excitotoxicity and oxidative stress are involved in neurodegenerative diseases, it becomes relevant to describe pharmacological therapies designed to activate endogenous cytoprotective systems. Activation of transcription factor Nrf2 stimulates cytoprotective vitagenes involved in antioxidant defense. In this work, we investigated the ability of the antioxidant curcumin to induce transcription factor Nrf2 in a neurodegenerative model induced by quinolinic acid in rats. Animals were administered with curcumin (400 mg/kg, p.o.) for 10 days, and then intrastriatally infused with quinolinic acid (240 nmol) on day 10 of treatment. Curcumin prevented rotation behavior (6 days post-lesion), striatal morphological alterations (7 days post-lesion) and neurodegeneration (1 and 3 days post-lesion) induced by quinolinic acid. Curcumin also reduced quinolinic acid-induced oxidative stress (measured as protein carbonyl content) at 6 h post-lesion. The protective effects of curcumin were associated to its ability to prevent the quinolinic acid-induced decrease of striatal intra-nuclear Nrf2 levels (30 and 120 min post-lesion), and total superoxide dismutase and glutathione peroxidase activities (1 day post-lesion). Therefore, results of this study support the concept that neuroprotection induced by curcumin is associated with its ability to activate the Nrf2 cytoprotective pathway and to increase the total superoxide dismutase and glutathione peroxidase activities.

Protective effect of L-kynurenine and probenecid on 6-hydroxydopamine-induced striatal toxicity in rats: implications of modulating kynurenate as a protective strategy.

The neuroactive metabolite at the kynunerine pathway, kynurenic acid (KYNA), is a well-known competitive antagonist at the co-agonist glycine site of the N-methyl-D-aspartate receptor (NMDAr), and also decreases the extracellular levels of glutamate by blocking α7-nicotinic acetylcholine receptor (α7-nAchr) located on glutamatergic terminals. KYNA has been often reported to be neuroprotective in different neurotoxic models. The systemic administration of L-kynurenine (L-KYN)--the precursor of KYNA--together with probenecid (PROB)--an inhibitor of organic acids transport--to rodents increases KYNA levels in the brain in a dose-dependent manner. The striatal infusion of the toxin 6-hydroxydopamine (6-OHDA) to rodents is one of the common models used to simulate Parkinson's disease (PD). Different studies have linked PD alterations with excessive glutamatergic transmission in the striatum since NMDAr antagonists exert beneficial effects in PD models. In this work we investigated the effect that a systemic administration of L-KYN+PROB exerted on the toxic model induced by 6-OHDA in rats. PROB (50 mg/kg, i.p.) + L-KYN (75 mg/kg, i.p.) were given to rats for seven consecutive days. On day two of treatment, the animals were infused with a single injection of 6-OHDA (20 µg/2 µl) into the right striatum. Fourteen days post-lesion, rotation behavior was assessed as a marker of motor impairment. The total levels of dopamine (DA) were also estimated in striatal tissue samples of 6-OHDA-treated animals as a neurochemical marker of damage. In addition, twenty eight days post-lesion, the striatal damage was assessed by hematoxylin/eosin staining and immunohistochemistry against glial fibrillary acidic protein (GFAP) in the same animals. Neurodegeneration was also assessed by Fluoro Jade staining. 6-OHDA infusion increased rotation behavior, striatal reactive gliosis and neurodegeneration, while DA levels were decreased. For all markers evaluated, we observed protective effects of L-KYN+PROB on the dopaminergic damage induced by 6-OHDA. Our results suggest that this strategy was useful to mitigate dopaminergic toxicity in the hemiparkinsonian model. The combined use of L-KYN and PROB is a valuable tool to modulate glutamatergic and cholinergic activities, presumably by means of increased levels of endogenous KYNA.

Protective effect of tert-butylhydroquinone on the quinolinic-acid-induced toxicity in rat striatal slices: role of the Nrf2-antioxidant response element pathway.

Tert-butylhydroquinone (tBHQ) is a xenobiotic with reported antioxidant properties. tBHQ has been shown to induce nuclear translocation of the transcription factor NF-E2-related factor 2 (Nrf2) to further activate the antioxidant response element (ARE). In turn, the Nrf2/ARE pathway is responsible for the induction of phase 2 antioxidant enzymes that detoxify oxidant promoters from different toxic insults. In this work, the antioxidant and protective actions of tBHQ were explored for the first time on different biomarkers of the neurotoxic model produced by the excitotoxic and pro-oxidant molecule quinolinic acid (QUIN) in rat striatal slices. For comparison purposes, 3-nitropropionic acid was used as reference model. Our results show that tBHQ (25 µM) prevented the QUIN-induced lipid peroxidation and mitochondrial dysfunction. In addition, tBHQ enhanced glutathione-S-transferase activity, partially recovering its depletion induced by QUIN treatment. Our results also demonstrated that tBHQ was able to induce nuclear accumulation of Nrf2 and further antioxidant protection: while QUIN alone decreased the nuclear Nrf2, a treatment with tBHQ preserved the nuclear levels Nrf2 in the presence of QUIN. Therefore, the tBHQ-mediated Nrf2/ARE induction constitutes a signaling-mediated antioxidant strategy and therapeutic tool to be tested in different neurotoxic models.

Potent activation of FGF-2 IRES-dependent mechanism of translation during brain development.

Fibroblast growth factor-2 (FGF-2) plays a fundamental role in brain functions. This role may be partly achieved through the control of its expression at the translational level via an internal ribosome entry site (IRES)-dependent mechanism. Transgenic mice expressing a bicistronic mRNA allowed us to study in vivo and ex vivo where this translational mechanism operates. Along brain development, we identified a stringent spatiotemporal regulation of FGF-2 IRES activity showing a peak at post-natal day 7 in most brain regions, which is concomitant with neuronal maturation. At adult age, this activity remained relatively high in forebrain regions. By the enrichment of this activity in forebrain synaptoneurosomes and by the use of primary cultures of cortical neurons or cocultures with astrocytes, we showed that this activity is indeed localized in neurons, is dependent on their maturation, and correlates with endogenous FGF-2 protein expression. In addition, this activity was regulated by astrocyte factors, including FGF-2, and spontaneous electrical activity. Thus, neuronal IRES-driven translation of the FGF-2 mRNA may be involved in synapse formation and maturation.

Indigestible starch associated to dietary fiber residues from cooked legume seeds consumed in Venezuela

El residuo fibroso de las semillas cocidas de once variedades de leguminosas comestibles fue preparado empleando el procedimiento enzimático de la AOAC. Una vez sometidos a un tratamiento de dispersión alcalina, dichos residuos fueron evaluados para determinar su contenido de almidón, que corresponde a fracciones de almodón resistente retrogradado (AR). Todas las leguminosas presentaron cantidades apreciadas de AR, cuyos valores variaron entre 3,0 por ciento (g por 100 g de semilla cocida en base seca), encontrado para el fr¡jol caupí, y 7,2 por ciento para las arvejas verdes. El tenor de AR difirió muy poco entre las cuatro variedades de fr¡jol común (Phaseolus vulgaris) analizadas ( 5,1-6,7 por ciento). El garbanzo también presentó valores considerables de AR (6,7 por ciento). Los tenores de AR se utilizaron para calcular el contenido de fibra insoluble descritos previamente para estas leguminosas. Dichos contenidos corregidos resultaron 11 a 38 por ciento menores que los valores originales.

Amino acid change 335 E to K affects the sialic-acid-binding and neuraminidase activities of Urabe AM9 mumps virus hemagglutinin-neuraminidase glycoprotein.

A mutation coding for the amino acid change E335 to K is frequently found in the hemagglutinin-neuraminidase (HN) gene of Urabe AM9 mumps viruses isolated during post-vaccination meningitis cases. To identify if this mutation modifies the biological activities of the HN glycoprotein, two variants of Urabe AM9 vaccine differing at amino acid 335 (HN-E335 and HN-K335) were isolated and their receptor-binding specificity was determined by means of competence assays. Pre-incubation of the viruses with sialic acids inhibited both syncytia formation in Vero cells and replication in SH-SY5Y cells. Thus, HN-K335 showed higher affinity towards sialylalpha2,6lactose, whereas HN-G335 preferred sialylalpha2,3lactose. These results are relevant because a high expression of sialylalpha2,6lactose in nerve cells was confirmed by means of Sambucus nigra lectin-cytochemistry. In addition, kinetics assays showed that HN-K335 and HN-E335 also differ in their hydrolysis rate (Vmax values of 37.5 vs. 3.5 nmol min-1mg-1, respectively). Therefore, HN-K335 variant presented a neuraminidase activity level 11-fold higher than that of HN-E335 variant. In conclusion, the mutation affects the receptor-binding and neuraminidase activities of Urabe AM9 mumps virus variants.

Testosterone regulates FGF-2 expression during testis maturation by an IRES-dependent translational mechanism.

Spermatogenesis is a complex process involving cell proliferation, differentiation, and apoptosis. Fibroblast growth factor 2 (FGF-2) is involved in testicular function, but its role in spermatogenesis has not been fully documented. The control of FGF-2 expression particularly occurs at the translational level, by an internal ribosome entry site (IRES)-dependent mechanism driving the use of alternative initiation codons. To study IRES activity regulation in vivo, we have developed transgenic mice expressing a bicistronic construct coding for two luciferase genes. Here, we show that the FGF-2 IRES is age-dependently activated in mouse testis, whereas EMCV and c-myc IRESs are not. Real-time PCR confirms that this regulation is translational. By using immunohistological techniques, we demonstrate that FGF-2 IRES stimulation occurs in adult, but not in immature, type-A spermatogonias. This is correlated with activation of endogenous FGF-2 expression in spermatogonia; whereas FGF-2 mRNA transcription is known to decrease in adult testis. Interestingly, the FGF-2 IRES activation is triggered by testosterone and is partially inhibited by siRNA directed against the androgen receptor. Two-dimensional analysis of proteins bound to the FGF-2 mRNA 5'UTR after UV cross-linking reveals that testosterone treatment correlates with the binding of several proteins. These data suggest a paracrine loop where IRES-dependent FGF-2 expression, stimulated by Sertoli cells in response to testosterone produced by Leydig cells, would in turn activate Leydig function and testosterone production. In addition, nuclear FGF-2 isoforms could be involved in an intracrine function of FGF-2 in the start of spermatogenesis, mitosis, or meiosis initiation. This report demonstrates that mRNA translation regulation by an IRES-dependent mechanism participates in a physiological process.

Características físicas y nutricionales de extrudidos de plátano verde (Musa spp), ocumo chino (Colocasia esculenta) y maíz (Zea mays L) / Physical and nutritional characteristics of green plantain (Musa spp), taro (Colocasia esculenta) and corn (Zea mays L) extrudates

El objetivo del presente trabajo fue evaluar las propiedades físicas y nutricionales de las harinas extrudidas de plátano verde, ocumo chino o taro y sus mezclas con maíz, para diversificar la producción y el uso potencial en la agroindustria. El plan de investigación se realizó con un extrusor de laboratorio, tipo monotornillo a una temperatura de alimentación 75 ºC, temperatura del barril y de la matriz 180 ºC, velocidad del tornillo 120 rpm y 16 por ciento en el contenido de humedad de las harinas. Bajo estas condiciones, se obtuvo a partir de la harina de plátano verde un extrudido de alta densidad y bajo índice de expansión, mientras que con las mezclas por separado de la harina de ocumo chino y de plátano verde con un 80 por ciento de la harina de maíz blanco, resultaron extrudidos con baja densidad y alto índice de expansión, encontrándose diferencias estadísticamente significativas (p< 0,05) en las medidas del color (“L”). Con relación a la composición nutricional, se determino que todos los extrudidos presentaron un alto contenido de almidón resistente (22 por ciento) y variaciones en el contenido de fibra dietética en el intervalo de 8,4 por ciento a 2,88 por ciento. En conclusión los extrudidos de plátano verde por su aporte en almidón resistente, fibra dietética y una digestión lenta del almidón, se podrían recomendar en alimentos precocidos para regimenes especiales de alimentación. La obtención de extrudidos de ocumo chino permitiría diversificar el uso potencial de este rubro en la industria de alimentos.

The object of the present study, was to evaluate the physical and nutritional properties of the extruded flours ofgreen plantain, taro, and their mixture with corn, to diversify the production and the potential use in the agro industry The researching plan was made with a laboratory extruder single screwed type; to a feeding temperature of 75 ºC, barrel and matrix temperature of 180 ºC, screw speed of 120 rpm, and an humidity content of 16 percent in the flours. Under these conditions, it was obtained an green plantain flour based extrusion, of high density and low ratio of expansion; in the meantime, the separated mixtures of taro and green plantain with an 80 percent white corn flour, gave as results extrudates with low density and high level of expansion, and statistically significant differences were found (p< 0,05) in the color measure (“L”). In relation with the nutritional composition, it was determined that all the extrudates presented a high content of resistant starch (22 percent), and variations in the content of dietary fiber in the interval from 8,4 percent to 2,88 percent. Finally, the green plantain extrudates, for their contribution in resistant starch, dietary fiber and slow digestion of starch; could be recommended in precooked foods for special nutrition regimes. The obtention of taro extrudates, would allow to diversify the potential use of this product in the food industry.

Hyperglycemia upregulates translation of the fibroblast growth factor 2 mRNA in mouse aorta via internal ribosome entry site.

Fibroblast growth factor 2 (FGF-2) is normally synthesized at low levels but is elevated in various pathophysiological conditions including diabetes-associated vascular diseases. FGF-2 expression is regulated translationally through an internal ribosome entry site (IRES) located in its mRNA, which allows a nonclassical cap-independent translation. We addressed the pathophysiological regulation of the IRES in vivo by using a streptozotocin-induced hyperglycemic model known to suppress markedly overall translation. Evaluation of FGF-2 IRES-dependent translation was performed with transgenic mice expressing dual luciferase bicistronic mRNA containing the FGF-2 IRES. FGF-2 IRES-dependent reporter activity increased 240% of control in the diabetic aorta although the reporter mRNA levels significantly decreased. Expression of endogenous FGF-2 protein in the aorta closely correlated with the IRES activity but not with FGF-2 mRNA levels. Moreover, the biosynthesis of endogenous FGF-2 protein was stimulated in an IRES-dependent manner by high glucose that significantly suppressed global protein synthesis in aortic smooth muscle cells from the transgenic mice. These results suggest that IRES-dependent translational regulation could play a pathological role in FGF-2 expression in vivo, especially in the cardiovascular consequences of diabetes.

Evaluación biológica de las arepas de maíz con arroz. Programa merienda escolar del Instituto Nacional de Nutrición / Biological evaluation of the corn and rice \"arepas\" included in the school lunch program of the Venezuelan Institute of Nutrition

El objetivo de este trabajo fue investigar el mejoramiento de la calidad de la proteína de la harina de maíz precocida para la elaboración de arepas, por medio del agregado de arroz precocido en los niveles 18 por ciento al 20 por ciento (mezcla A) de la merienda escolar del Instituto Nacional de Nutrición (INN) " Mi Criollita", 8 por ciento al 10 por ciento (mezcla B), comparándola con la harina de maíz comercial (C) y caseína como dieta control. Los efectos de esta adición fueron evaluados por el método del valor proteico relativo. Dietas con niveles de proteínas de aproximadamente 3,5 por ciento, 5,5 por ciento y 7,5 por ciento con harinas elaboradas a partir de arepas y dietas control de caseína, fueron ofrecidas a ratas de experimentación en crecimiento. Los coeficientes de regresión de las líneas de regresión lineal de crecimiento en relación con la ingesta de proteinas, demostraron un mejoramiento moderado de la calidad de la proteína de las mezclas. Esta conclusión fue corroborada por la alta correlación entre el nivel de arroz agregado, el crecimiento de losanimales y el Valor Proteico Relativo: 34 por ciento mezcla A, 25 por ciento mezcla B, 5 por ciento harina C, al compararlos con la caseína a la cual se le signó el valor 100 por ciento