Efecto protector del aceite de oliva sobre la activación de la Microglía

Un posible enfoque terapéutico para el tratamiento de enfermedades neuroinflamatorias se podría basar en la inhibición del fenotipo de la microglía M1 mientras se estimula el fenotipo M2. Nuestra hipótesis es que el tipo de ácidos graso (FA) de la dieta en las lipoproteínas ricas en triglicéridos (TRL) postprandiales humanas podría modular la plasticidad de la microglía. Para ello, aislamos las TRL en el pico hipertrigliceridémico postprandial de muestras de sangre de voluntarios sanos trás la ingesta de una comida rica en FAs saturados (SFAs), FAs monoinsaturados (MUFAs) o MUFAs más FAs poliinsaturados de cadena larga omega-3 (PUFAs). Observamos que las TRL-MUFAs potencian la polarización hacia microglía M2, mientras que las TRL-SFAs hacen que la microglía sea polarizada a un fenotipo M1. Además, en comparación con los SFAs de la dieta, los MUFAs produjeron un perfil proinflamatorio menor en el cerebro de los ratones alimentados con una dieta rica en grasa. Nuestro estudio subraya el papel de las TRL postprandiales como una entidad metabólica en la regulación de la plasticidad de la microglía y ofrece una comprensión de los mecanismos por los cuales los FAs de la dieta juegan un papel en la respuesta inmune innata en el sistema nervioso central. Del mismo modo evaluamos los efectos neuroprotectores de compuestos menores encontrados en la fracción insaponificable (UF) y en la fracción fenólica (PF) del aceite de oliva virgen (VOO) en células microgliales BV2 y en el cerebro de ratones con obesidad inducida por dieta alta en grasas (HFD) a través de RT-qPCR, ELISA y técnicas de citometría de flujo. Observamos que la UF y la PF potencian la polarización de la microglía hacia un fenotipo M2, mientras que la microglía estimulada con LPS es propensa al fenotipo M1. Además, en comparación con los SFAs de la dieta, el VOO produjo un perfil proinflamatorio menor en el cerebro de los ratones. Estos interesantes hallazgos abren nuevas oportunidades para desarrollar estrategias nutracéuticas con el aceite de oliva como la fuente principal de MUFAs, especialmente el ácido oleico, y de los compuestos menores del aceite de oliva virgen para prevenir el desarrollo y la progresión de enfermedades relacionadas con la neuroinflamación

Nutraceutical Extract from Dulse (Palmaria palmata L.) Inhibits Primary Human Neutrophil Activation

Palmaria palmata L. (Palmariaceae), commonly known as "dulse", is a red alga that grows on the northern coasts of the Atlantic and Pacific oceans, and is widely used as source of fiber and protein. Dulse is reported to contain anti-inflammatory and antioxidant compounds, albeit no study has investigated these effects in primary human neutrophils. Implication strategies to diminish neutrophil activation have the potential to prevent pathological states. We evaluated the ability of a phenolic dulse extract (DULEXT) to modulate the lipopolysaccharide (LPS)-mediated activation of primary human neutrophils. Intracellular reactive oxygen species (ROS) were measured by fluorescence analysis and nitric oxide (NO) production using the Griess reaction. Inflammatory enzymes and cytokines were detected by ELISA and RT-qPCR. The results show that DULEXT diminished the neutrophil activation related to the down-regulation of TLR4 mRNA expression, deceased gene expression and the LPS-induced release of the chemoattractant mediator IL-8 and the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. ROS, NO, and myeloperoxidase (MPO) were also depressed. The data indicated that DULEXT has the potential to disrupt the activation of human primary neutrophils and the derived inflammatory and prooxidant conditions, and suggest a new role for Palmaria palmata L. in the regulation of the pathogenesis of health disorders in which neutrophils play a key role, including atherosclerosisSpanish Ministry of Science, Innovation and Universities grant CYTED-2019 119RT056

Minor compounds from virgin olive oil attenuate LPS-induced inflammation via visfatin-related gene modulation on primary human monocytes

We have analyzed the effects of minor compounds found in the unsaponifiable fraction (UF) and in the phenolic fraction (PF) of virgin olive oil (VOO) on LPS-induced inflammatory response via visfatin modulation in human monocytes. For this purpose, monocytes were incubated with UF and PF at different concentrations and the pro-inflammatory stimulus LPS for 24 hr; squalene (SQ) and hydroxytyrosol (HTyr), the main components in UF and PF, respectively, were also used. The relative expression of both pro-inflammatory and anti-inflammatory genes, as well as other genes related to the NAD+-biosynthetic pathway was evaluated by RT-qPCR; and the secretion of some of these markers was assessed by ELISA procedures. We found that UF, SQ, PF, and HTyr prevented from LPS-induced dysfunctional gene expression and secretion via visfatin-related gene modulation in human monocytes. These findings unveil a potential beneficial role for minor compounds of VOO in the prevention of inflammatory-disorders. Practical application: In this project, potential health benefits of VOO micronutrients (unsaponifiable and phenolic compounds) were confirmed through anti-inflammatory assays. Our results reveal new interesting researching goals concerning nutrition by considering the role of bioactive VOO compounds in the prevention and progress of diseases related to inflammation

Nutritional composition, ultrastructural characterization, and peptidome profile of antioxidant hemp protein hydrolysates

Hemp is the term commonly used to refer to the variety of Cannabis sativa L. cultivated for industrial purposes. The seeds have gained interest in recent years as functional foods due to their nutritional composition and high content of protein and bioactive compounds. In this study, ten hemp protein hydrolysates (HPHs) were obtained by enzymatic hydrolysis with Alcalase and Flavourzyme from hemp protein isolate (HPI) and their antioxidant properties (DPPH radical scavenging activity, beta-carotene activity and ferric ion reducing antioxidant power (FRAP)) were evaluated. Shorter peptide sequences, mainly obtained with Flavourzyme, were found to react with free radicals more easily. The peptidome of all the hydrolysates was characterized, identifying, and quantifying the peptides. Furthermore, 19 unique peptides were assessed by in silico tools to hypothesize those that could be responsible of the bioactivity reported for the hydrolysates. From the identified peptides, based on the molecular features and the predictions, the peptides KNAIYTPH, EERPGHF, and KNGMMAPH, among others, are proposed to be highly contributing to the antioxidant activity of the hydrolysates.Junta de Andalucía US-138149

GPETAFLR, a biopeptide from Lupinus angustifolius L., protects against oxidative and inflammatory damage in retinal pigment epithelium cells

GPETAFLR, an octapeptide released from the enzymatic hydrolysis of lupine (Lupinus angustifolius L.) protein, has demonstrated anti-inflammatory effect in myeloid lineage. This work aims to evaluate in retinal pigment epithelium (RPE) cells the protective role of GPETAFLR on both oxidative and inflammatory markers known to be involved in age-related macular degeneration (AMD). In comparison with stimulated control cells, GPETAFLR increased glutathione production and diminished the secretion and gene expression of VEFG, IL-1β, IL-6, IFNγ, and TNF-α, as well as reactive oxygen species, and nitrite output. Our findings reveal that GPETAFLR, a novel plant peptide, is able to protect against RPE oxidative stress and inflammation. Taken together, these results strongly support innovative nutritional strategies considering Lupinus angustifolius L. as source of proteins to prevent the onset and progression of AMD. Practical applications: We reveal a novel nutraceutical impact of GPETAFLR peptide in human RPE cells to prevent oxidative and inflammatory mediators. Our results support that the intake of Lupine angustifolius L., proposed to be a reservoir of GPETAFLR, could lessen the functional decay of RPE cells, leading therefore to a slowdown of the progress of AMD during age. Not only this work, but also future simple clinical studies should raise new nutritional strategies focused on understanding the etiological role of the foods, nutrition, and metabolism in the pathogenesis of ocular disorders.Ministerio de Economía y Competitividad AGL2012‐40247‐C02‐0

Obesity-associated metabolic disturbances reverse the antioxidant and anti-inflammatory properties of high-density lipoproteins in microglial cells

High-density lipoproteins (HDLs) play an important role in reverse cholesterol transport and present antioxidant properties, among others. In the central nervous system (CNS), there are HDLs, where these lipoproteins could influence brain health. Owing to the new evidence of HDL functionality remodeling in obese patients, and the fact that obesity-associated metabolic disturbances is pro-inflammatory and pro-oxidant, the aim of this study was to investigate if HDL functions are depleted in obese patients and obesity-associated microenvironment. HDLs were isolated from normal-weight healthy (nwHDL) and obese men (obHDL). The oxHDL level was measured by malondialdehyde and 4-hydroxynoneal peroxided products. BV2 microglial cells were exposed to different concentrations of nwHDL and obHDL in different obesity-associated pro-inflammatory microenvironments. Our results showed that hyperleptinemia increased oxHDL levels. In addition, nwHDLs reduced pro-inflammatory cytokines’ release and M1 marker gene expression in BV2 microglial cells. Nevertheless, both nwHDL co-administered with LPS+leptin and obHDL promoted BV2 microglial activation and a higher pro-inflammatory cytokine production, thus confirming that obesity-associated metabolic disturbances reverse the antioxidant and anti-inflammatory properties of HDLs in microglial cells.Junta de Andalucía US-126345

COVID-19 after two years : trajectories of different components of mental health in the Spanish population

Our study aimed to (1) identify trajectories on different mental health components during a two-year follow-up of the COVID-19 pandemic and contextualise them according to pandemic periods; (2) investigate the associations between mental health trajectories and several exposures, and determine whether there were differences among the different mental health outcomes regarding these associations. We included 5535 healthy individuals, aged 40-65 years old, from the Barcelona Brain Health Initiative (BBHI). Growth mixture models (GMM) were fitted to classify individuals into different trajectories for three mental health-related outcomes (psychological distress, personal growth and loneliness). Moreover, we fitted a multinomial regression model for each outcome considering class membership as the independent variable to assess the association with the predictors. For the outcomes studied we identified three latent trajectories, differentiating two major trends, a large proportion of participants was classified into 'resilient' trajectories, and a smaller proportion into 'chronic-worsening' trajectories. For the former, we observed a lower susceptibility to the changes, whereas, for the latter, we noticed greater heterogeneity and susceptibility to different periods of the pandemic. From the multinomial regression models, we found global and cognitive health, and coping strategies as common protective factors among the studied mental health components. Nevertheless, some differences were found regarding the risk factors. Living alone was only significant for those classified into 'chronic' trajectories of loneliness, but not for the other outcomes. Similarly, secondary or higher education was only a risk factor for the 'worsening' trajectory of personal growth. Finally, smoking and sleeping problems were risk factors which were associated with the 'chronic' trajectory of psychological distress. Our results support heterogeneity in reactions to the pandemic and the need to study different mental health-related components over a longer follow-up period, as each one evolves differently depending on the pandemic period. In addition, the understanding of modifiable protective and risk factors associated with these trajectories would allow the characterisation of these segments of the population to create targeted interventions

Functional brain connectivity prior to the COVID-19 outbreak moderates the effects of coping and perceived stress on mental health changes. A first year of COVID-19 pandemic follow-up study

The COVID-19 pandemic provides a unique opportunity to investigate the psychological impact of a global major adverse situation. Our aim was to study, in a longitudinal prospective, the demographic, psychological and neurobiological factors associated with inter-individual differences in resilience to mental health pandemic impact. We included 2,023 healthy participants (age: 54.32±7.18 years, 65.69% females) from the Barcelona Brain Health Initiative cohort. A linear mixed model was used to characterize the change in anxiety and depression symptoms based on the collected pre- and during-COVID-19 data. During pandemic, psychological variables assessing individual differences in perceived stress and coping strategies were obtained. Additionally, in a subsample (N=433, age:53.02 ± 7.04 years, 46.88% females) with pre-pandemic resting-state functional magnetic resonance imaging available, networks' system segregation (SyS) was calculated. Multivariate linear models were fitted to test associations between COVID-19-related changes in mental health and demographics, psychological features and brain networks status. The whole sample showed a general increase in anxiety and depressive symptoms after the pandemic onset, and both age and sex were independent predictors. Coping strategies attenuated the impact of perceived stress on mental health. SyS of fronto-parietal control and default mode networks were found to modulate the impact of perceived stress on mental health. Preventive strategies destined for the promotion of mental health at an individual's level during future similar adverse events should consider intervening on sociodemographic and psychological factors, as well as their interplay with neurobiological substrates

Acyclic Diterpene Phytol from Hemp Seed Oil (Cannabis sativa L.) Exerts Anti-Inflammatory Activity on Primary Human Monocytes-Macrophages

Seeds from non-drug varieties of hemp (Cannabis sativa L.) have been used for traditional medicine, food, and fiber production. Our study shows that phytol obtained from hemp seed oil (HSO) exerts anti-inflammatory activity in human monocyte-macrophages. Fresh human monocytes and human macrophages derived from circulating monocytes were used to evaluate both plasticity and anti-inflammatory effects of phytol from HSO at 10–100 mM using FACS analysis, ELISA, and RT-qPCR methods. The quantitative study of the acyclic alcohol fraction isolated from HSO shows that phytol is the most abundant component (167.59 ± 1.81 mg/Kg of HSO). Phytol was able to skew monocyte-macrophage plasticity toward the anti-inflammatory non-classical CD14+CD16++ monocyte phenotype and toward macrophage M2 (CD200Rhigh and MRC-1high), as well as to reduce the production of IL-1β, IL-6, and TNF-α, diminishing the inflammatory competence of mature human macrophages after lipopolysaccharide (LPS) treatment. These findings point out for the first time the reprogramming and anti-inflammatory activity of phytol in human monocyte-macrophages. In addition, our study may help to understand the mechanisms by which phytol from HSO contributes to the constant and progressive plasticity of the human monocyte-macrophage linage

Postprandial triglyceride-rich lipoproteins promote M1/M2 microglia polarization in a fatty acid-dependent manner

6 Figuras.-- 1 TablaInhibiting M1 microglia phenotype while stimulating the M2 microglia has been suggested as a potential therapeutic approach for the treatment of neuroinflammatory diseases. Our hypothesis is that the type of dietary fatty acids (FAs) into human postprandial triglyceride-rich lipoproteins (TRLs) could modulate the plasticity of microglia. We isolated TRLs at the postprandial hypertriglyceridemic peak from blood samples of healthy volunteers after the ingestion of a meal rich in saturated FAs (SFAs), monounsaturated FAs (MUFAs) or MUFAs plus omega-3 long-chain polyunsaturated FAs. We observed that postprandial TRL-MUFAs enhance M2 microglia polarization, whereas postprandial TRL-SFAs made polarized microglia prone to an M1 phenotype. In addition, in contrast to dietary SFAs, dietary MUFAs primed for a reduced proinflammatory profile in the brain of mice fed with the different FA-enriched diets. Our study underlines a role of postprandial TRLs as a metabolic entity in regulating the plasticity of microglia and brings an understanding of the mechanisms by which dietary FAs are environmental factors fostering the innate immune responsiveness. These exciting findings open opportunities for developing nutraceutical strategies with olive oil as the principal source of MUFAs, notably oleic acid, to prevent development and progression of neuroinflammation-related diseases.Authors thank Cell Biology Unit of Instituto de la Grasa for its assistance during the fulfillment of this work. S.M.P. acknowledges financial support from “V Own Research Plan” (University of Seville)