SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer's Disease.

Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer's disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1ß, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.

A dietary polyphenol metabolite alters CA1 excitability ex vivo and mildly affects cortico-hippocampal field potential generators in anesthetized animals.

Dietary polyphenols have beneficial effects in situations of impaired cognition in acute models of neurodegeneration. The possibility that they may have a direct effect on the electrical activity of neuronal populations has not been tested. We explored the electrophysiological action of protocatechuic acid (PCA) on CA1 pyramidal cells ex vivo and network activity in anesthetized female rats using pathway-specific field potential (FP) generators obtained from laminar FPs in cortex and hippocampus. Whole-cell recordings from CA1 pyramidal cells revealed increased synaptic potentials, particularly in response to basal dendritic excitation, while the associated evoked firing was significantly reduced. This counterintuitive result was attributed to a marked increase of the rheobase and voltage threshold, indicating a decreased ability to generate spikes in response to depolarizing current. Systemic administration of PCA only slightly altered the ongoing activity of some FP generators, although it produced a striking disengagement of infraslow activities between the cortex and hippocampus on a scale of minutes. To our knowledge, this is the first report showing the direct action of a dietary polyphenol on electrical activity, performing neuromodulatory roles at both the cellular and network levels.

Selection of Enzymatic Treatments for Upcycling Lentil Hulls into Ingredients Rich in Oligosaccharides and Free Phenolics.

In this study, the comprehensive chemical characterization of red lentil hulls obtained from the industrial production of football and split lentils was described. The lentil hulls were rich in dietary fiber (78.43 g/100 g dry weight with an insoluble to soluble fiber ratio of 4:1) and polyphenols (49.3 mg GAE/g dry weight, of which 55% was bound phenolics), which revealed the suitability of this lentil by-product as a source of bioactive compounds with recognized antioxidant and prebiotic properties. The release of oligosaccharides and phenolic compounds was accomplished by enzymatic hydrolysis, microwave treatment and a combination of both technologies. The key role played by the selection of a suitable enzymatic preparation was highlighted to maximize the yield of bioactive compounds and the functional properties of the lentil hull hydrolysates. Out of seven commercial preparations, the one with the most potential for use in a commercial context was Pectinex® Ultra Tropical, which produced the highest yields of oligosaccharides (14 g/100 g lentil hull weight) and free phenolics (45.5 mg GAE/100 g lentil hull weight) and delivered a four-fold increase in terms of the original antioxidant activity. Finally, this enzyme was selected to analyze the effect of a microwave-assisted extraction pretreatment on the yield of enzymatic hydrolysis and the content of free phenolic compounds and oligosaccharides. The integrated microwave and enzymatic hydrolysis method, although it increased the solubilization yield of the lentil hulls (from 25% to 34%), it slightly decreased the content of oligosaccharides and proanthocyanidins and reduced the antioxidant activity. Therefore, the enzymatic hydrolysis treatment alone was more suitable for producing a lentil hull hydrolysate enriched in potential prebiotics and antioxidant compounds.

Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA.

The screening of the BCR::ABL1 kinase domain (KD) mutation has become a routine analysis in case of warning/failure for chronic myeloid leukemia (CML) and B-cell precursor acute lymphoblastic leukemia (ALL) Philadelphia (Ph)-positive patients. In this study, we present a novel DNA-based next-generation sequencing (NGS) methodology for KD ABL1 mutation detection and monitoring with a 1.0E-4 sensitivity. This approach was validated with a well-stablished RNA-based nested NGS method. The correlation of both techniques for the quantification of ABL1 mutations was high (Pearson r = 0.858, p < 0.001), offering DNA-DeepNGS a sensitivity of 92% and specificity of 82%. The clinical impact was studied in a cohort of 129 patients (n = 67 for CML and n = 62 for B-ALL patients). A total of 162 samples (n = 86 CML and n = 76 B-ALL) were studied. Of them, 27 out of 86 harbored mutations (6 in warning and 21 in failure) for CML, and 13 out of 76 (2 diagnostic and 11 relapse samples) did in B-ALL patients. In addition, in four cases were detected mutation despite BCR::ABL1 < 1%. In conclusion, we were able to detect KD ABL1 mutations with a 1.0E-4 sensitivity by NGS using DNA as starting material even in patients with low levels of disease.

Prolactin Reduces Hippocampal Parvalbumin and GABAA Receptor Expression in Female Mice.

INTRODUCTION: Parvalbumin (PV)-positive cells are strategic elements of neuronal networks capable of influencing memory and learning processes. However, it is not known whether pituitary hormones may be related to PV expression in the hippocampus - a part of the limbic system with important functions in learning and memory. OBJECTIVE: Since previous studies indicate that prolactin (PRL) plays a significant role in hippocampal-dependent learning and synaptic plasticity, we hypothesized that a rise in PRL levels can modify PV expression in the hippocampus. METHODS: We employed biochemical, immunohistochemistry, and densitometry techniques - as well as a behavioural assay - in a hyperprolactinemia model using subcutaneous osmotic pumps in female mice. RESULTS: PRL treatment via osmotic pump induced an increase in PRL receptor (PRLR) expression in most regions of the hippocampus analysed by Western blotting and immunohistochemistry methods. Fluorescent densitometry analysis revealed that PV expression decreases in the same layers in the hippocampus following PRL treatment, while double labelling immunostaining indicated close localization of PV and PRLR in PV-positive interneurons. In addition, we found that PRL induced a reduction in the ß2/3 subunit of GABAA receptor (GABAAR) expression that was linearly correlated with the reduction in PV expression. This reduction in the ß2/3 subunit of GABAAR expression was maintained in trained animals in which PRL treatment improved the learning of a spatial memory task. CONCLUSIONS: These data show, for the first time, that an increase in PRL level is associated with changes in key constituent elements of inhibitory circuits in the hippocampus and may be of relevance for the alterations in cognitive function reported in hyperprolactinemia.

Lentil and Fava Bean With Contrasting Germination Kinetics: A Focus on Digestion of Proteins and Bioactivity of Resistant Peptides.

Germination offers advantages to improve legume protein digestibility as it disintegrates seed structure and hydrolyzes proteins and anti-nutrients. Seed permeability (related to polyphenol content of seed coats) is an important factor affecting the duration of seed germination and its impact on protein digestibility and bioactivity. The objective was to compare the effect of seed germination on protease activity, structure, and proteolysis of four selected legumes with contrasting seed coat polyphenol profiles (gray zero-tannin lentil [GZL], beluga lentil [BL], and dehulled red lentil [DL]; and zero tannin/low vicine-convicine fava bean [ZF]). Protein hydrolysis was characterized during germination and digestion with respect to proteins, peptides, and free amino acids (FAAs). In vitro antihypertensive and antioxidant activities of digests were investigated, and the peptidomic characterization [high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS)] and identification of bioactive fragments in intestinal digests were performed. Regardless of the seed type, germination increased protease activity and reduced the levels of phytic acid, trypsin inhibitors, and tannins (only in BL). A significant proteolysis of the 7S and 11S globulins and a concomitant increase of peptides and FAAs were observed in all sprouted legumes. Digestion kinetics in sprouts revealed a faster generation of FAAs and peptides than in dry seeds, with changes being more evident for DL, associated with a faster imbibition, germination, and sprout growth. In contrast, BL sprouts showed the lowest protein digestibility, likely due to a lower protease activity, seed structure disintegration, and higher anti-nutrient levels in comparison to GZL, DL, and ZF. Moreover, the digestion of sprouts resulted in a higher number of resistant peptides in DL and ZF that matched with previously reported bioactive sequences, suggesting a promising health potential of legume sprouts that was confirmed in vitro. The results suggested that the germination process improved protein digestibility and the health-promoting potential of lentil and fava bean proteins although these changes were more evident in DL due to its rapid imbibition, faster germination, and sprout development. This study will provide important information for either plant breeders to develop legume varieties with permeable seed coats or food producers that could use dehulled seeds for efficient production of sprouts as sustainable food sources of plant proteins with improved nutritional and healthy properties.

Enzyme Selection and Hydrolysis under Optimal Conditions Improved Phenolic Acid Solubility, and Antioxidant and Anti-Inflammatory Activities of Wheat Bran.

Valorization of wheat bran (WB) into new high-value products is of great interest within the framework of sustainability and circular economy. In the present study, we utilized a multi-step approach to extract nutraceutical compounds (phenolic acids) from WB and improved its antioxidant and anti-inflammatory properties through using sequential hydrothermal and enzymatic hydrolysis. Thirteen commercial glycosidases differing in their specific activity were screened and compared for hydrolytic efficiency to release monosaccharides, ferulic acid, and diferulic acid. Ultraflo XL was selected as the desired enzyme treatment on the basis of its higher WB solubilization, as well as its monosaccharide and phenolic acids yields. The relationships between better hydrolytic performance of Ultraflo XL and its particular activity profile were established. To determine the optimum conditions for Ultraflo XL treatment, we tested different factors (solvent pH, incubation temperature, and time) under 15 experiments. A multicomponent analysis (MCA), including central composite design, model fitness, regression coefficients, analysis of variance, 3D response curves, and desirability, was used for processing optimization. A beneficial effect of autoclave treatment on the release of phenolic compounds was also evidenced. The results of MCA showed involvement of linear, quadratic, and interactive effects of processing factors, although solvent pH was the main determinant factor, affecting enzymatic extraction of phenolics and bioactivity of hydrolysates. As compared to control WB, under optimized conditions (47 °C, pH = 4.4, and 20.8 h), WB hydrolysates showed 4.2, 1.5, 2, and 3 times higher content of ferulic acid (FA) and capacity to scavenge oxygen radicals, chelate transition metals, and inhibit monocyte chemoattractant protein-1 secretion in macrophages, respectively. These approaches could be applied for the sustainable utilization of WB, harnessing its nutraceutical potential.

Soluble Phenolic Composition Tailored by Germination Conditions Accompany Antioxidant and Anti-inflammatory Properties of Wheat.

Knowledge on the specific variation in the phenolic composition of wheat defined by germination conditions and its relationship with antioxidant and anti-inflammatory properties of sprouts would be useful to improve the functional value of wheat-derived products. Variation in soluble phenolic composition, antioxidant and anti-inflammatory potential of wheat was examined in a range of germination temperature (12-21 °C) and time (1-7 d). Response surface methodology was applied for building lineal and quadratic models to find optimal germination conditions to improve nutraceutical value of wheat sprouts using the desirability (D) function. Phenolics were determined by HPLC-DAD-ESI-MS. In vitro biochemical methods and lipopolysaccharide stimulated RAW264.7 macrophages were used to determine antiradical and anti-inflammatory activities of wheat sprouts. Accumulation of soluble phenolic acids, flavone C-glycosides and lignans in sprouts was positively influenced by germination temperature and time. Increased concentration of individual polyphenols was directly associated with improved ability of sprouts for radical scavenging and reduction of tumor necrosis factor α and interleukin 6 in macrophages. Optimal desirability (D = 0.89) for improved nutraceutical value of wheat sprouts was achieved at 21 °C for 7 d. This information would be useful for food industry aiming at producing wheat-based products with better nutritional and healthy properties.

Pilot-scale produced fermented lentil protects against t-BHP-triggered oxidative stress by activation of Nrf2 dependent on SAPK/JNK phosphorylation.

Fermented lentil (FL) produced using L. plantarum and Savinase in alkaline conditions relieves metabolic alterations and oxidative stress in Zucker rats with metabolic syndrome. Here, we investigated the effect of up scaling the fermentation process on chemical composition and biological activity of FL. Moreover, we studied the molecular mechanisms by which FL exert a cytoprotective effect against oxidative stress in tert-butyl hydroperoxide (t-BHP)-challenged RAW264.7 macrophages. Up-scale production reduced overall biological effectiveness of FL with the exception of inhibition of intracellular ROS generation. FL prevented t-BHP-induced cytotoxicity and intracellular accumulation of reactive oxygen species through activation of catalase expression via SAPK/JNK phosphorylation and Nrf2 nuclear translocation. Different oligopeptides, phenolic acids and flavonols were identified as contributors of the observed effects. To the best of our knowledge, we reported for the first time that FL attenuates oxidative stress cellular damage via activation of SAPK/JNK phosphorylation, Nrf2 nuclear translocation and antioxidant enzymes expression.

Individual contributions of Savinase and Lactobacillus plantarum to lentil functionalization during alkaline pH-controlled fermentation.

Legumes offer the possibility to develop multifunctional foods with benefits for metabolic syndrome. Our objective was to study the effect of alkaline fermentation by Lactobacillus plantarum and Savinase (FLPS) as well the individual effects of both processes on peptides, phenolics and bioactivity of lentil. FLPS increased peptides and some flavonoids and enhanced antioxidant activity, inhibition of angiotensin I-converting enzyme (ACE) and intestinal maltase activities of lentil soluble fraction. Savinase contributed to peptide release, ACE inhibitory and antioxidant activities of lentil soluble fraction. L. plantarum affected to phenolic composition, α-glucosidase and lipase inhibitory activities. Mass spectrometry analysis of the most active fermented lentil subfraction allowed the identification of the main bioactive compounds. Gastrointestinal digestion of fermented lentil increased bioaccessibility of peptides and phenolics as well as antioxidant activity. FLPS enhanced the overall healthy potential of lentil offering the possibility of its use as strategy for lentil functionalization.

pH-controlled fermentation in mild alkaline conditions enhances bioactive compounds and functional features of lentil to ameliorate metabolic disturbances.

Lentil fermentation has a promising potential as a strategy for development of multifunctional ingredients targeting metabolic syndrome (MetS). Response surface methodology was applied to optimize lentil fermentation and study its effects on generation of peptides, soluble phenolics and bioactivities. Fermentation using Lactobacillus plantarum and Savinase® 16 L was carried out at different pH (6.5-8.5) and times (5.5-30 h). Analysis of variance was performed to evaluate linear, quadratic and interaction effects between fermentation parameters. pH positively affected peptides, soluble phenolic compounds and antioxidant activity whereas a negative impact on lipase inhibitory activity was observed (p < .0001). Time showed positive effect on proteolysis and negatively affected angiotensin I-converting enzyme inhibitory activity of fermented lentil (p < .0001). Multivariate optimization led to high levels of peptides, soluble phenolics and bioactivity of fermented lentil at pH 8.5 and 11.6 h. In conclusion, this study might contribute to the development of functional ingredients from lentil for MetS management.

Perfiles de orientación hacia la meta y su relación con indicadores de actividad físico-deportiva / Goal Orientation Profiles and Their Relation with Indicators of Physical Activity

Resumen El presente estudio examinó la motivación hacia la actividad física empleando la teoría de la orientación hacia la meta. Un total de 786 estudiantes participaron en este estudio. Un procedimiento de análisis de cluster jerárquico permitió identificar cuatro perfiles de orientación hacia la meta. El perfil más adaptativo (alta tarea/alto ego/altas expectativas) se asoció con la obtención de los mejores resultados. Se concluye que los jóvenes con una alta motivación hacia la tarea, alto ego y expectativas de ejecución obtienen las mayores muestras de apoyo por parte de familiares e iguales para la práctica de actividad física se perciben más autoeficaces para realizar dicha actividad, se atribuyen una mejor forma física autopercibida y manifiestan una práctica más frecuente de actividad físico-deportiva.

Abstract This paper researches motivation for physical activity in the framework of the goal orientation theory. This work is based on data from 786 students. Hierarchical cluster analysis allowed identifying four goal orientation profiles. The most adaptive profile (high task, high ego, high expectancy) is associated with the best results. Students with high motivation for physical activity, ego, and performance expectancy are concluded to obtain more indications of support from their relatives and peers for physical activity practice, perceive themselves self-effective to complete this activity, claim their better self-perceived fitness, and show more frequent physical-sports activity.