Attenuation of Autism-like Behaviors by an Anthocyanin-Rich Extract from Portuguese Blueberries via Microbiota-Gut-Brain Axis Modulation in a Valproic Acid Mouse Model.

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental pathologies whose current treatment is neither curative nor effective. Anthocyanins are naturally occurring compounds abundant in blueberries and in other red fruits which have been shown to be successful in the treatment of several neurological diseases, at least in in vitro and in vivo disease models. The aim of the present work was to study the ability of an anthocyanin-rich extract (ARE) obtained from Portuguese blueberries to alleviate autism-like symptoms in a valproic acid (VPA) mouse model of ASD and to get insights into the underlying molecular mechanisms of such benefits. Therefore, pregnant BALB/c females were treated subcutaneously with a single dose of VPA (500 mg/kg) or saline on gestational day 12.5. Male offspring mice were orally treated with the ARE from Portuguese blueberries (30 mg/kg/day) or the vehicle for three weeks, and further subjected to behavioral tests and biochemical analysis. Our data suggested that the ARE treatment alleviated autism-like behaviors in in utero VPA-exposed mice and, at the same time, decreased both neuroinflammation and gut inflammation, modulated the gut microbiota composition, increased serotonin levels in cerebral prefrontal cortex and gut, and reduced the synaptic dysfunction verified in autistic mice. Overall, our work suggests that anthocyanins extracted from Portuguese blueberries could constitute an effective strategy to ameliorate typical autistic behaviors through modulation of the microbiota-gut-brain axis.

The Anti-Neuroinflammatory Role of Anthocyanins and Their Metabolites for the Prevention and Treatment of Brain Disorders.

Anthocyanins are naturally occurring polyphenols commonly found in fruits and vegetables. Numerous studies have described that anthocyanin-rich foods may play a crucial role in the prevention and treatment of different pathological conditions, which have encouraged their consumption around the world. Anthocyanins exhibit a significant neuroprotective role, mainly due to their well-recognized antioxidant and anti-inflammatory properties. Neuroinflammation is an intricate process relevant in both homeostatic and pathological circumstances. Since the progression of several neurological disorders relies on neuroinflammatory process, targeting brain inflammation has been considered a promising strategy in those conditions. Recent data have shown the anti-neuroinflammatory abilities of many anthocyanins and of their metabolites in the onset and development of several neurological disorders. In this review, it will be discussed the importance and the applicability of these polyphenolic compounds as neuroprotective agents and it will be also scrutinized the molecular mechanisms underlying the modulation of neuroinflammation by these natural compounds in the context of several brain diseases.

Polyphenols in the management of brain disorders: Modulation of the microbiota-gut-brain axis.

The modulation of the microbiota-gut-brain axis with a view to preventing and treating brain disorders became recently a hot topic for the scientific community. Dietary polyphenols are multifaceted compounds that have demonstrated to be highly advantageous to counteract inflammation, oxidative stress, and neurodegeneration, among other pathological conditions, being useful in the prevention and treatment of several chronic disorders. The potential of these compounds to prevent and treat brain disorders has not been only related to their capacity to reach the brain, depending on their chemical structure, and interact directly with brain cells, but also to their ability to modulate the communication between the brain and the gut, interfering with multiple branches of this axis. Preclinical studies have demonstrated the potential of these food bioactive compounds in brain diseases, namely, neurodevelopmental, such as Down's syndrome and Autism spectrum disorder, neurodegenerative, such as Parkinson's disease and Alzheimer's disease, and psychiatric disorders, such as depression and anxiety. Until now, dietary polyphenols have been recognized as promising nutraceuticals to combat brain disorders. However, the impact of these compounds on the gut-brain interconnection remains poorly elucidated. Also, clinical assays are crucial to further support the beneficial effects of these compounds as demonstrated in preclinical research.

An Anthocyanin-Rich Extract Obtained from Portuguese Blueberries Maintains Its Efficacy in Reducing Microglia-Driven Neuroinflammation after Simulated Digestion.

Dietary polyphenols are multi-target compounds that have been considered promising candidates in strategies for the mitigation of neurological diseases, acting particularly through reduction of microglia-driven neuroinflammation. In this study, an anthocyanin-rich extract obtained from Portuguese blueberries was subjected to a simulated gastrointestinal digestion; after chemical characterisation, the potential of both non-digested and digested extracts to combat neuroinflammation was evaluated using a microglia N9 cell line. Although the extracts have markedly different chemical composition, both were efficient in reducing the production of either key inflammatory markers or reactive oxygen species and in enhancing reduced glutathione levels in activated cells. Furthermore, this protection was shown to be related to the suppression of nuclear factor kappa B (NF-kB) activation, and to a signal transducer and activator of transcription 1 (STAT1)-independent mechanism. These results demonstrate that the anthocyanin extract, after simulated digestion, maintains its efficacy against neuroinflammation, and can, therefore, assume a relevant role in prevention of neuroinflammation-related neurological disorders.

The Impact of Chronic Intestinal Inflammation on Brain Disorders: the Microbiota-Gut-Brain Axis.

It has been shown that the gut microbiota plays a crucial role in the maintenance of intestinal homeostasis. Additionally, it has been demonstrated that dysbiosis is closely correlated with chronic intestinal inflammation, contributing to the development of chronic intestinal diseases, and also of brain pathologies, including neurodegenerative, neurodevelopmental, and psychiatric disorders. Given the paramount importance of gut microbiota for the establishment of communication between the gut and the brain, the microbiota-gut-brain axis has been increasingly explored within the scope of neurosciences. In this review article, we present an overview of key cellular signaling pathways underlying chronic intestinal inflammation and the influence of chronic intestinal inflammation and dysbiosis on brain disorders. This will include the presentation of valuable data from recent preclinical and clinical research. We will also address the importance of probiotics and prebiotics to targeting the microbiota-gut-brain axis in the context of some brain disorders, where they are seen to be promising strategies for ameliorating brain disorders.

Polyphenols as food bioactive compounds in the context of Autism Spectrum Disorders: A critical mini-review.

Dietary polyphenols are bioactive compounds with potential in preventing and treating several chronic disorders, mainly due to their ability to modulate key pro-inflammatory and pro-oxidant signalling pathways. Although some studies have expressed concern about their efficacy in vivo, accumulating evidence has suggested that these compounds may achieve large concentrations in the gastrointestinal tract, which may be important in the context of intestinal and of neurological disorders, via modulation of the "gut-brain axis". Autism Spectrum disorders (ASD) are a group of lifelong neurodevelopmental disorders in which many patients suffer from gastrointestinal impairments. Thus, in the scope of these disorders, a growing number of studies have been focused on the microbiota-gut-brain axis. In this mini-review, we present gathered data on gut-to-brain communication in the scope of ASD and we address the advantages of polyphenols in the treatment of these disorders, presenting the more recent preclinical and clinical data on this issue. According to most studies, dietary polyphenols can be a promising strategy for the alleviation of ASD symptoms.

Anti-inflammatory protection afforded by cyanidin-3-glucoside and resveratrol in human intestinal cells via Nrf2 and PPAR-γ: Comparison with 5-aminosalicylic acid.

This study investigated the involvement of nuclear factor erythroid 2 (Nrf2) and peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathways in the protection afforded by two polyphenols abundant in diet, cyanidin-3-glucoside and resveratrol, against cytokine-induced inflammation and oxidative insult in HT-29 intestinal cells, in comparison with the drug 5-aminosalicylic acid (5-ASA). Our data show for the first time that in cytokine-challenged cells, cyanidin-3-glucoside and resveratrol induced Nrf2 activation, increased hemoxygenase-1 and glutamate cysteine ligase mRNA expression, enhanced reduced glutathione to oxidized glutathione ratio and inhibited reactive species production, at much lower concentrations than 5-ASA. Unlike cyanidin-3-glucoside, resveratrol and 5-ASA also increased nuclear levels of PPAR-γ in cytokine-stimulated cells. In conclusion, both polyphenols might be interesting as nutraceuticals, giving complementary benefits to conventional drugs against intestinal inflammation, typically present in patients with inflammatory bowel disease.

Red wine polyphenol extract efficiently protects intestinal epithelial cells from inflammation via opposite modulation of JAK/STAT and Nrf2 pathways.

The development of therapeutic approaches combining efficacy and safety represents an important goal in intestinal inflammation research. Recently, evidence has supported dietary polyphenols as useful tools in the treatment and prevention of chronic inflammatory diseases, but the mechanisms of action are still poorly understood. We here reveal molecular mechanisms underlying the anti-inflammatory action of a non-alcoholic polyphenol red wine extract (RWE), operating at complementary levels via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and Nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways. RWE significantly reduced the nuclear levels of phosphorylated STAT1 and also the cellular levels of phosphorylated JAK1 induced by cytokines, suppressing the JAK/STAT inflammatory signalling cascade. In turn, RWE increased the Nrf2 nuclear level, activating the Nrf2 pathway, leading not only to an up-regulation of the heme oxygenase-1 (HO-1) expression but also to an increase of the glutamate-cysteine ligase subunit catalytic (GCLc) gene expression, enhancing the GSH synthesis, thereby counteracting GSH depletion that occurs under inflammatory conditions. Overall, data indicate that the anti-inflammatory action of RWE is exerted at complementary levels, via suppression of the JAK/STAT inflammatory pathway and positive modulation of the activity of Nrf2. These results point to the potential use of the RWE as an efficient, readily available and inexpensive therapeutic strategy in the context of gastrointestinal inflammation.

Resveratrol modulates cytokine-induced Jak/STAT activation more efficiently than 5-aminosalicylic acid: an in vitro approach.

BACKGROUND: Many advances have been recently made focused on the valuable help of dietary polyphenols in chronic inflammatory diseases. On the other hand, current treatment options for intestinal bowel disease patients are unsatisfying and, for this reason, it is estimated that many patients use dietary supplements to achieve extra benefits. AIM: The aim of this work was to analyze under a mechanistic perspective the anti-inflammatory potential of resveratrol, a natural polyphenolic compound, and to compare it with a pharmaceutical agent, 5-aminosalicylic acid, using the intestinal HT-29 cell line, as a cellular model. METHODOLOGY AND PRINCIPAL FINDINGS: In the present study, HT-29 colon epithelial cells were pre-treated with 25 µM resveratrol and/or 500 µM 5-aminosalicylic acid and then exposed to a combination of cytokines (IL-1α, TNF-α, IFN-γ) for a certain period of time. Our data showed that resveratrol, used in a concentration 20 times lower than 5-aminosalicylic acid, was able to significantly reduce NO and PGE2 production, iNOS and COX-2 expression and reactive oxidant species formation induced by the cytokine challenge. However, as already verified with 5-aminosalicylic acid, in spite of not exhibiting any effect on IkB-α degradation, resveratrol down-regulated JAK-STAT pathway, decreasing the levels of activated STAT1 in the nucleus. Additionally, resveratrol decreased the cytokine-stimulated activation of SAPK/JNK pathway but did not counteract the cytokine-triggered negative feedback mechanism of STAT1, through p38 MAPK. CONCLUSION/SIGNIFICANCE: Taken together, our results show that resveratrol may be considered a future nutraceutical approach, promoting remission periods, limiting the inflammatory process and preventing colorectal cancer, which is common in these patients.

Cyanidin-3-glucoside suppresses cytokine-induced inflammatory response in human intestinal cells: comparison with 5-aminosalicylic acid.

The potential use of polyphenols in the prevention and treatment of chronic inflammatory diseases has been extensively investigated although the mechanisms involved in cellular signaling need to be further elucidated. Cyanidin-3-glucoside is a typical anthocyanin of many pigmented fruits and vegetables widespread in the human diet. In the present study, the protection afforded by cyanidin-3-glucoside against cytokine-triggered inflammatory response was evaluated in the human intestinal HT-29 cell line, in comparison with 5-aminosalicylic acid, a well-established anti-inflammatory drug, used in inflammatory bowel disease. For this purpose, some key inflammatory mediators and inflammatory enzymes were examined. Our data showed that cyanidin-3-glucoside reduced cytokine-induced inflammation in intestinal cells, in terms of NO, PGE2 and IL-8 production and of iNOS and COX-2 expressions, at a much lower concentration than 5-aminosalicylic acid, suggesting a higher anti-inflammatory efficiency. Interestingly, cyanidin-3-glucoside and 5-aminosalicylic acid neither prevented IkB-α degradation nor the activation of NF-kB, but significantly reduced cytokine-induced levels of activated STAT1 accumulated in the cell nucleus. In addition, we established that phosphorylated p38 MAPK was not involved in the protective effect of cyanidin-3-glucoside or 5-aminosalicylic acid. Taking into account the high concentrations of dietary anthocyanins potentially reached in the gastrointestinal tract, cyanidin-3-glucoside may be envisaged as a promising nutraceutical giving complementary benefits in the context of inflammatory bowel disease.

Composition of a volatile extract of Eryngium duriaei subsp. juresianum (M. Laínz) M. Laínz, signalised by the antifungal activity.

The composition of a volatile extract of Eryngium duriaei subsp. juresianum, signalised by the antifungal activity (MIC values=0.16-0.32 µL mL(-1)) against several dermatophyte species (Trichophyton mentagrophytes, T. rubrum, Epidermophyton floccosum; T. verrucosum, T. mentagrophytes var interdigitale, Microsporum canis and M. gypseum) was established following a combined methodology of GC, GC-MS and an exclusive (13)C NMR technique that does not require prior isolation of compounds. Twenty-five components were identified accounting 84.6% of the whole composition. Major compound was found to be α-neocallitropsene (26.0%) although the dominance of caryophyllane derived compounds, the most probable responsible for the antifungal activity, namely isocaryophyllen-14-al (16.2%), 14-hidroxy-ß-caryophyllene (13.4%), caryophyllene oxide (7.6%) and E-ß-caryophyllene (6.3%).